Aminopyrimidines as ALK inhibitors

ABSTRACT

The present disclosure provides compounds represented by Formula I: 
                         
and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , and R 7  are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat a condition or disorder responsive to inhibition of ALK such as cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of Ser. No. 15/559,445 filed Sep. 19,2017, which is a U.S. national phase of PCT/US17/48845, filed Aug. 28,2017, which claims the benefit of 62/380,818, filed Aug. 29, 2016.

BACKGROUND OF THE INVENTION Field of the Invention

The present disclosure provides anaplastic lymphoma kinase inhibitorsand therapeutic methods of treating conditions and diseases whereininhibition of anaplastic lymphoma kinase provides a benefit.

Background

Anaplastic lymphoma kinase (ALK), a member of the insulin receptorsuperfamily of receptor tyrosine kinases, has been implicated inoncogenesis in hematopoietic and non-hematopoietic tumors. The aberrantexpression of full-length ALK receptor proteins has been reported inneuroblastomas and glioblastomas; and ALK fusion proteins have occurredin anaplastic large cell lymphoma. The study of ALK fusion proteins hasalso raised the possibility of new therapeutic treatments for patientswith ALK-positive malignancies. Pulford et al., Cell. Mol. Life. Sci.61:2939-2953 (2004).

Small molecule ALK inhibitors have therapeutic potential for thetreatment of diseases and conditions in which ALK has a role, includingcancer. Roskoski, Pharmacological Research 68:68-94 (2013). ALKinhibitors are disclosed in U.S. Pat. No. 8,039,479 and WO 2015/130014.

There is an ongoing need for new agents, e.g., small molecules, fortreating and/or preventing cancer and other diseases responsive to ALKinhibition.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides compounds represented byany one of Formulae I-VI, below, and the pharmaceutically acceptablesalts and solvates thereof, collectively referred to as “Compounds ofthe Disclosure.” Compounds of the Disclosure are ALK inhibitors and arethus useful in treating or preventing diseases or conditions wherein ALKinhibition provides a benefit.

In another aspect, the present disclosure provides methods of treatingor preventing a condition or disease by administering a therapeuticallyeffective amount of a Compound of the Disclosure to an individual, e.g.,a human, in need thereof. The disease or condition of interest istreatable or preventable by inhibition of ALK, for example, a cancer, achronic autoimmune disorder, an inflammatory condition, a proliferativedisorder, sepsis, or a viral infection. Also provided are methods ofpreventing the proliferation of unwanted proliferating cells, such as incancer, in a subject comprising administering a therapeuticallyeffective amount of a Compound of the Disclosure to a subject at risk ofdeveloping a condition characterized by unwanted proliferating cells. Insome embodiments, the Compounds of the Disclosure may reduce theproliferation of unwanted cells by inducing apoptosis in those cells.

In another aspect, the present disclosure provides a method ofinhibiting ALK in an individual, comprising administering to theindividual an effective amount of at least one Compound of theDisclosure.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a Compound of the Disclosure and an excipientand/or pharmaceutically acceptable carrier.

In another aspect, the present disclosure provides a compositioncomprising a Compound of the Disclosure and an excipient and/orpharmaceutically acceptable carrier for use treating or preventingdiseases or conditions wherein inhibition of ALK provides a benefit,e.g., cancer.

In another aspect, the present disclosure provides a compositioncomprising: (a) a Compound of the Disclosure; (b) a secondtherapeutically active agent; and (c) optionally an excipient and/orpharmaceutically acceptable carrier.

In another aspect, the present disclosure provides a Compound of theDisclosure for use in treatment or prevention of a disease or conditionof interest, e.g., cancer.

In another aspect, the present disclosure provides a use of a Compoundof the Disclosure for the manufacture of a medicament for treating adisease or condition of interest, e.g., cancer.

In another aspect, the present disclosure provides a kit comprising aCompound of the Disclosure, and, optionally, a packaged compositioncomprising a second therapeutic agent useful in the treatment of adisease or condition of interest, and a package insert containingdirections for use in the treatment of a disease or condition, e.g.,cancer.

In another aspect, the present disclosure provides methods of preparingCompounds of the Disclosure.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF DRAWINGS

FIG. 1 is a line graph showing Cpd. Nos. 5 and 6 inhibit tumor growth inthe KARPAS 299 xenograph model in mice.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the Disclosure are ALK inhibitors.

In one embodiment, Compounds of the Disclosure are compounds representedby Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R^(1a) and R^(1b) are independently selected from the group consistingof hydrogen, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl;

R^(2a) and R^(2b) are independently selected from the group consistingof hydrogen, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl;

R³ is selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and C₄₋₈ heterocyclo,

R⁴ is selected from the group consisting of C₁₋₄ alkyl and C₃₋₆cycloalkyl;

R⁵ is halo;

R⁶ is selected from the group consisting of C₁₋₄ alkyl and C₃₋₆cycloalkyl; and

R⁷ is selected from the group consisting of hydrogen, C₁₋₄ alkyl, andC₃₋₆ cycloalkyl,

with proviso that when R^(1a), R^(1b), R^(2a), and R^(2b) are eachhydrogen, then R³ is selected from the group consisting of C₃₋₆cycloalkyl and C₄₋₈ heterocyclo.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R^(1a) and R^(1b) are independently selected from the group consistingof hydrogen, C₁₋₄ alkyl, and C₃₋₆ cycloalkyl;

R^(2a) and R^(2b) are independently selected from the group consistingof hydrogen, C₁₋₄ alkyl, and C₃₋₆ cycloalkyl; and

R³ is selected from the group consisting of hydrogen, C₁₋₄ alkyl, C₃₋₆cycloalkyl, and C₄₋₈ heterocyclo,

with proviso that when R^(1a), R^(1b), R^(2a), and R^(2b) are eachhydrogen, then R³ is selected from the group consisting of C₃₋₆cycloalkyl and C₄₋₈ heterocyclo.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I or II, with proviso that when R^(1a), R^(1b),R^(2a), and R^(2b) are each hydrogen, then R³ is C₄₋₈ heterocyclo.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I or II, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(1b) and R^(2b) are each hydrogen.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I or II, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(1a), R^(1b), R^(2a), and R^(2b) are eachhydrogen.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I or II, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(1b) and R^(2b) are each hydrogen; and R^(1a)and R^(2a) are each C₁₋₄ alkyl. In another embodiment, R^(1a) and R^(2a)are each methyl. In another embodiment, R^(1a) and R^(2a) have a cisstereochemical relationship. In another embodiment, R^(1a) and R^(2a)have a trans stereochemical relationship.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I or II, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(1b) and R^(2b) are each hydrogen; and R^(1a)and R^(2a) are each C₃₋₆ cycloalkyl. In another embodiment, R^(1a) andR^(2a) are each cyclopropyl. In another embodiment, R^(1a) and R^(2a)have a cis stereochemical relationship. In another embodiment, R^(1a)and R^(2a) have a trans stereochemical relationship.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I or II, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(1a), R^(1b), R^(2a), and R^(2b) are eachC₁₋₃ alkyl. In another embodiment, R^(1a), R^(1b), R^(2a), and R^(2b)are each methyl.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula III:

or a pharmaceutically acceptable salt or solvate thereof, wherein thecompound has an enantiomeric excess of about 90% or more; R^(1a) andR^(2a) are each independently C₁₋₄ alkyl, or C₃₋₆ cycloalkyl; and R³ isas defined in connection with Formula II. In another embodiment, thecompound has an enantiomeric excess of about 91% or more, about 92% ormore, about 93% or more, about 94% or more, about 95% or more, about 96%or more, about 97% or more, about 98% or more, or about 99% or more.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula IV:

or a pharmaceutically acceptable salt or solvate thereof, wherein thecompound has an enantiomeric excess of about 90% or more; R^(1a) andR^(2a) are each independently C₁₋₄ alkyl, or C₃₋₆ cycloalkyl; and R³ isas defined in connection with Formula II. In another embodiment, thecompound has an enantiomeric excess of about 91% or more, about 92% ormore, about 93% or more, about 94% or more, about 95% or more, about 96%or more, about 97% or more, about 98% or more, or about 99% or more.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein thecompound has an enantiomeric excess of about 90% or more; R^(1a) andR^(2a) are each independently C₁₋₄ alkyl, or C₃₋₆ cycloalkyl; and R³ isas defined in connection with Formula II. In another embodiment, thecompound has an enantiomeric excess of about 91% or more, about 92% ormore, about 93% or more, about 94% or more, about 95% or more, about 96%or more, about 97% or more, about 98% or more, or about 99% or more.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula VI:

or a pharmaceutically acceptable salt or solvate thereof, wherein thecompound has an enantiomeric excess of about 90% or more; R^(1a) andR^(2a) are each independently C₁₋₄ alkyl, or C₃₋₆ cycloalkyl; and R³ isas defined in connection with Formula II. In another embodiment, thecompound has an enantiomeric excess of about 91% or more, about 92% ormore, about 93% or more, about 94% or more, about 95% or more, about 96%or more, about 97% or more, about 98% or more, or about 99% or more.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formula III-VI, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(1a) and R^(2a) are eachC₁₋₃ alkyl. In another embodiment, R^(1a) and R^(2a) are each methyl.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formula III-VI, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(1a) and R^(2a) are eachC₃₋₆ cycloalkyl. In another embodiment, R^(1a) and R^(2a) are eachcyclopropyl.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formula I-VI, or a pharmaceutically acceptablesalt or solvate thereof, wherein R³ is hydrogen.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formula I-VI, or a pharmaceutically acceptablesalt or solvate thereof, wherein R³ is C₁₋₃ alkyl. In anotherembodiment, R³ is methyl.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formula I-VI, or a pharmaceutically acceptablesalt or solvate thereof, wherein R³ is C₃₋₆ heterocyclo. In anotherembodiment, R³ is C₃₋₆ heterocyclo selected from the group consistingof:

In another embodiment, Compounds of the Disclosure are compounds ofTable 1, and the pharmaceutically acceptable salts and solvates thereof.The compounds of Table 1 are racemates.

TABLE 1 Cpd. No. Structure Name 1

5-chloro-N2-(2-isopropoxy-5-methyl-4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridin- 4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 2

5-chloro-N2-(2-isopropoxy-5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 3

5-chloro-N2-(4-((cis)-2,6-diethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 4

5-chloro-N2-(4-((cis)-2,6-diethyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 5

5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 6

5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 7

5-chloro-N2-(4-((cis)-2,6-dicyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 8

5-chloro-N2-(4-((cis)-2,6-dicyclobutyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 9

5-chloro-N2-(4-((cis)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 10

5-chloro-N2-(2-isopropoxy-5-methyl-4-((cis)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 11

5-chloro-N2-(4-((trans)-2,6-diethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 12

5-chloro-N2-(4-((trans)-2,6-diethyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 13

5-chloro-N2-(4-((trans)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 14

5-chloro-N2-(2-isopropoxy-5-methyl-4-((trans)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 15

5-chloro-N2-(4-((cis)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 16

5-chloro-N2-(4-((cis)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 17

5-chloro-N2-(4-((trans)-2,6-dicyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 18

5-chloro-N2-(4-((trans)-2,6-dicyclobutyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 19

5-chloro-N2-(4-((trans)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 20

5-chloro-N2-(4-((trans)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 21

5-chloro-N2-(4-((cis)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 22

5-chloro-N2-(4-((cis)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy- 5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 23

5-chloro-N2-(4-((trans)-2,6-diethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 24

5-chloro-N2-(4-((2S,6S)-2,6-diethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy- 5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 25

5-chloro-N2-(4-((trans)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 26

5-chloro-N2-(4-((trans)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 27

5-chloro-N2-(4-((cis)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 28

5-chloro-N2-(4-((cis)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 29

5-chloro-N2-(4-((trans)-2,6-dicyclobutyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 30

5-chloro-N2-(4-((trans)-2,6-dicyclobutyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 31

5-chloro-N2-(4-((trans)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 32

5-chloro-N2-(4-((trans)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine

In another embodiment, Compounds of the Disclosure are compounds ofTable 2, and the pharmaceutically acceptable salts and solvates thereof.The compounds of Table 2 are enantiomerically enriched.

TABLE 2 Cpd. No. Structure Name 33

5-chloro-N2-(4-((2S,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 34

5-chloro-N2-(2-isopropoxy-5-methyl-4-((2S,6R)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 35

5-chloro-N2-(4-((2R,6R)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 36

5-chloro-N2-(4-((2R,6R)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 37

5-chloro-N2-(4-((2R,6S)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 38

5-chloro-N2-(2-isopropoxy-5-methyl-4-((2R,6S)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 39

5-chloro-N2-(4-((2S,6S)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 40

5-chloro-N2-(2-isopropoxy-5-methyl-4-((2S,6S)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 41

5-chloro-N2-(4-((2R,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 42

5-chloro-N2-(2-isopropoxy-5-methyl-4- ((2R,6R)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 43

5-chloro-N2-(4-((2S,6S)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 44

5-chloro-N2-(4-((2S,6S)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 45

5-chloro-N2-(4-((2R,6S)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 46

5-chloro-N2-(4-((2R,6S)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 47

5-chloro-N2-(4-((2S,6R)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 48

5-chloro-N2-(4-((2S,6R)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 49

5-chloro-N2-(4-((2R,6S)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 50

5-chloro-N2-(4-((2R,6S)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 51

5-chloro-N2-(4-((2S,6S)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 52

5-chloro-N2-(4-((2S,6S)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 53

5-chloro-N2-(4-((2R,6R)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 54

5-chloro-N2-(4-((2R,6R)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 55

5-chloro-N2-(4-((2S,6S)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 56

5-chloro-N2-(4-((2S,6S)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 57

5-chloro-N2-(4-((2R,6S)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 58

5-chloro-N2-(4-((2R,6S)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 59

5-chloro-N2-(4-((2S,6R)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine 60

5-chloro-N2-(4-((2S,6R)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine

In another embodiment, a Compound of the Disclosure is5-chloro-N²-(2-isopropoxy-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine,or a pharmaceutically acceptable salt or hydrate thereof.

Compounds of the Disclosure inhibit ALK and are useful in the treatmentor prevention of a variety of diseases and conditions. In particular,Compounds of the Disclosure are useful in methods of treating orpreventing a disease or condition wherein inhibition of ALK provides abenefit, for example, cancers and proliferative diseases. Thetherapeutic methods of this disclosure comprise administering atherapeutically effective amount of a Compound of the Disclosure to anindividual in need thereof. The present methods also encompassadministering a second therapeutic agent to the individual in additionto the Compound of the Disclosure. The second therapeutic agent isselected from drugs known as useful in treating the disease or conditionafflicting the individual in need thereof, e.g., a chemotherapeuticagent and/or radiation known as useful in treating a particular cancer.

Certain of the Compounds of the Disclosure may exist as stereoisomers,i.e., isomers that differ only in the spatial arrangement of atoms,including optical isomers and conformational isomers (or conformers) andtautomers. The disclosure includes all stereoisomers, both as pureindividual stereoisomer preparations and enriched preparations of each,and both the racemic mixtures of such stereoisomers as well as theindividual diastereomers and enantiomers that may be separated accordingto methods that are well known to those of skill in the art.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” or “asymmetric carbon atom” refers to a carbonatom to which four different groups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” or “racemate” refers to a mixture of equal parts ofenantiomers and which mixture is optically inactive.

The term “absolute configuration” refers to the spatial arrangement ofthe atoms of a chiral molecular entity (or group) and its stereochemicaldescription, e.g., R or S.

The stereochemical terms and conventions used in the specification aremeant to be consistent with those described in Pure & Appl. Chem 68:2193(1996), unless otherwise indicated.

The term “enantiomeric excess” or “ee” refers to a measure for how muchof one enantiomer is present compared to the other. For a mixture of Rand S enantiomers, the percent enantiomeric excess is defined as|R−S|*100, where R and S are the respective mole or weight fractions ofenantiomers in a mixture such that R+S=1. With knowledge of the opticalrotation of a chiral substance, the percent enantiomeric excess isdefined as ([α]_(obs)/[α]_(max))*100, where [α]_(obs) is the opticalrotation of the mixture of enantiomers and [α]_(max) is the opticalrotation of the pure enantiomer. Determination of enantiomeric excess ispossible using a variety of analytical techniques, including NMRspectroscopy, chiral column chromatography or optical polarimetry.Certain compounds of the Disclosure can have an ee of about 70% or more,e.g., about 80% or more, about 90% or more, about 91% or more, about 92%or more, about 93% or more, about 94% or more, about 95% or more, about96% or more, about 97% or more, about 98% or more, or about 99% or more,

The terms “enantiomerically pure” or “enantiopure” refer to a sample ofa chiral substance all of whose molecules (within the limits ofdetection) have the same chirality sense.

The terms “enantiomerically enriched” or “enantioenriched” refer to asample of a chiral substance whose enantiomeric ratio is greater than50:50. In Enantiomerically enriched compounds may be enantiomericallypure.

Salts, hydrates, and solvates of the Compounds of the Disclosure canalso be used in the methods disclosed herein. The present disclosureencompasses the preparation and use of salts of Compounds of theDisclosure. As used herein, the pharmaceutical “pharmaceuticallyacceptable salt” refers to salts or zwitterionic forms of Compounds ofthe Disclosure. Salts of Compounds of the Disclosure can be preparedduring the final isolation and purification of the compounds orseparately by reacting the compound with an acid having a suitablecation. The pharmaceutically acceptable salts of Compounds of theDisclosure can be acid addition salts formed with pharmaceuticallyacceptable acids. Examples of acids which can be employed to formpharmaceutically acceptable salts include inorganic acids such asnitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, andorganic acids such as oxalic, maleic, succinic, and citric. Nonlimitingexamples of salts of compounds of the disclosure include, but are notlimited to, the hydrochloride, hydrobromide, hydroiodide, sulfate,bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate,acetate, adipate, alginate, asp artate, benzoate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerolphosphate,hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate,maleate, ascorbate, isethionate, salicylate, methanesulfonate,mesitylenesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate,trifluoroacetate, phosphate, glutamate, bicarbonate,paratoluenesulfonate, undecanoate, lactate, citrate, tartrate,gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, andp-toluenesulfonate salts. In addition, available amino groups present inthe compounds of the disclosure can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides. Inlight of the foregoing, any reference Compounds of the Disclosureappearing herein is intended to include compounds of Compounds of theDisclosure as well as pharmaceutically acceptable salts, hydrates, orsolvates thereof.

The present disclosure encompasses the preparation and use of solvatesof Compounds of the Disclosure. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present disclosure with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present disclosure is about 2:1, about 1:1or about 1:2, respectively. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances, the solvate can be isolated, such as when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate” encompasses both solution-phase andisolatable solvates. Compounds of the Disclosure can be present assolvated forms with a pharmaceutically acceptable solvent, such aswater, methanol, and ethanol, and it is intended that the disclosureincludes both solvated and unsolvated forms of Compounds of theDisclosure.

One type of solvate is a hydrate. A “hydrate” relates to a particularsubgroup of solvates where the solvent molecule is water. Solvatestypically can function as pharmacological equivalents. Preparation ofsolvates is known in the art. See, for example, M. Caira et al, J.Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparationof solvates of fluconazole with ethyl acetate and with water. Similarpreparation of solvates, hemisolvates, hydrates, and the like aredescribed by van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12(2004), and A. L. Bingham et al., Chem. Commun. 603-604 (2001). Atypical, non-limiting, process of preparing a solvate would involvedissolving a Compound of the Disclosure in a desired solvent (organic,water, or a mixture thereof) at temperatures above 20° C. to about 25°C., then cooling the solution at a rate sufficient to form crystals, andisolating the crystals by known methods, e.g., filtration. Analyticaltechniques such as infrared spectroscopy can be used to confirm thepresence of the solvent in a crystal of the solvate.

The present disclosure provides Compounds of the Disclosure asinhibitors of ALK for the treatment of a variety of diseases andconditions wherein inhibition has a beneficial effect. Compounds of theDisclosure typically have a binding affinity (IC₅₀) to ALK of less than100 μM, e.g., less than about 50 μM, less than about 25 μM, and lessthan about 5 μM, less than about 1 less than about 0.5 less than about0.1 less than about 0.05 μM, less than about 0.01 μM, less than about0.005 μM, or less than about 0.001 μM. In one embodiment, the presentdisclosure relates to a method of treating an individual suffering froma disease or condition wherein inhibition of ALK provides a benefitcomprising administering a therapeutically effective amount of aCompound of the Disclosure to an individual in need thereof.

Since Compounds of the Disclosure are ALK inhibitors, a number ofdiseases and conditions mediated by ALK can be treated by employingthese compounds. The present disclosure is thus directed generally to amethod for treating a condition or disorder responsive to inhibition ofALK, or an isoform or mutant thereof, in an animal, e.g., a humanpatient, suffering from, or at risk of suffering from, the condition ordisorder, the method comprising administering to the animal an effectiveamount of one or more Compounds of the Disclosure.

The present disclosure is further directed to a method of inhibitingALK, or an isoform or mutant thereof, in an animal in need thereof, saidmethod comprising administering to the animal an effective amount of atleast one Compound of the Disclosure.

The methods of the present disclosure can be accomplished byadministering a Compound of the Disclosure as the neat compound or as apharmaceutical composition. Administration of a pharmaceuticalcomposition, or neat compound of a Compound of the Disclosure, can beperformed during or after the onset of the disease or condition ofinterest. Typically, the pharmaceutical compositions are sterile, andcontain no toxic, carcinogenic, or mutagenic compounds that would causean adverse reaction when administered.

Further provided are kits comprising a Compound of the Disclosure and,optionally, a second therapeutic agent useful in the treatment ofdiseases and conditions wherein inhibition of ALK, or an isoform ormutant thereof, provides a benefit, packaged separately or together, andan insert having instructions for using these active agents.

In one embodiment, a Compound of the Disclosure is administered inconjunction with a second therapeutic agent useful in the treatment of adisease or condition wherein inhibition of ALK proteins provides abenefit. The second therapeutic agent is different from the Compound ofthe Disclosure. A Compound of the Disclosure and the second therapeuticagent can be administered simultaneously or sequentially to achieve thedesired effect. In addition, the Compound of the Disclosure and secondtherapeutic agent can be administered from a single composition or twoseparate compositions.

The second therapeutic agent is administered in an amount to provide itsdesired therapeutic effect. The effective dosage range for each secondtherapeutic agent is known in the art, and the second therapeutic agentis administered to an individual in need thereof within such establishedranges.

A Compound of the Disclosure and the second therapeutic agent can beadministered together as a single-unit dose or separately as multi-unitdoses, wherein the Compound of the Disclosure is administered before thesecond therapeutic agent or vice versa. One or more doses of theCompound of the Disclosure and/or one or more dose of the secondtherapeutic agent can be administered. The Compound of the Disclosuretherefore can be used in conjunction with one or more second therapeuticagents, for example, but not limited to, anticancer agents.

Diseases and conditions treatable by the methods of the presentdisclosure include, but are not limited to, cancer and otherproliferative disorders, inflammatory diseases, sepsis, autoimmunedisease, and viral infection. In one embodiment, Diseases and conditionstreatable by the methods of the present disclosure are cancer, a chronicautoimmune disorder, an inflammatory condition, or a proliferativedisorder. In one embodiment, a human patient is treated with a Compoundof the Disclosure, or a pharmaceutical composition comprising a Compoundof the Disclosure, wherein the compound is administered in an amountsufficient to inhibit ALK in the patient.

In one embodiment, the disease to be treated or prevented by theCompound of the Disclosure is cancer. In another embodiment, the presentdisclosure provides a method of treating or preventing cancer in asubject in need thereof comprising administering a therapeuticallyeffective amount of a Compound of the Disclosure to the subject. Whilenot being limited to a specific mechanism, in some embodiments,Compounds of the Disclosure can treat or prevent cancer by inhibitingALK. Examples of treatable cancers include, but are not limited to, anyone or more of the cancers of Table 3.

TABLE 3 adrenal cancer lymphoepithelioma acinic cell carcinoma lymphomaacoustic neuroma acute lymphocytic leukemia acral lentigious melanomaacute myelogeous leukemia acrospiroma chronic lymphocytic leukemia acuteeosinophilic leukemia liver cancer acute erythroid leukemia small celllung cancer acute lymphoblastic leukemia non-small cell lung canceracute megakaryoblastic leukemia MALT lymphoma acute monocytic leukemiamalignant fibrous histiocytoma acute promyelocytic leukemia malignantperipheral nerve sheath tumor adenocarcinoma malignant triton tumoradenoid cystic carcinoma mantle cell lymphoma adenoma marginal zoneB-cell lymphoma adenomatoid odontogenic tumor mast cell leukemiaadenosquamous carcinoma mediastinal germ cell tumor adipose tissueneoplasm medullary carcinoma of the breast adrenocortical carcinomamedullary thyroid cancer, adult T-cell leukemia/lymphoma medulloblastomaaggressive NK-cell leukemia melanoma, AIDS-related lymphoma meningioma,alveolar rhabdomyosarcoma merkel cell cancer alveolar soft part sarcomamesothelioma ameloblastic fibroma metastatic urothelial carcinomaanaplastic large cell lymphoma mixed Mullerian tumor anaplastic thyroidcancer mucinous tumor angioimmunoblastic T-cell lymphoma, multiplemyeloma angiomyolipoma muscle tissue neoplasm angiosarcoma mycosisfungoides astrocytoma myxoid liposarcoma atypical teratoid rhabdoidtumor myxoma B-cell chronic lymphocytic leukemia myxosarcoma B-cellprolymphocytic leukemia nasopharyngeal carcinoma B-cell lymphomaneurinoma basal cell carcinoma neuroblastoma biliary tract cancerneurofibroma bladder cancer neuroma blastoma nodular melanoma bonecancer ocular cancer Brenner tumor oligoastrocytoma Brown tumoroligodendroglioma Burkitt's lymphoma oncocytoma breast cancer opticnerve sheath meningioma brain cancer optic nerve tumor carcinoma oralcancer carcinoma in situ osteosarcoma carcinosarcoma ovarian cancercartilage tumor Pancoast tumor cementoma papillary thyroid cancermyeloid sarcoma paraganglioma chondroma pinealoblastoma chordomapineocytoma choriocarcinoma pituicytoma choroid plexus papillomapituitary adenoma clear-cell sarcoma of the kidney pituitary tumorcraniopharyngioma plasmacytoma cutaneous T-cell lymphoma polyembryomacervical cancer precursor T-lymphoblastic lymphoma colorectal cancerprimary central nervous system lymphoma Degos disease primary effusionlymphoma desmoplastic small round cell tumor preimary peritoneal cancerdiffuse large B-cell lymphoma prostate cancer dysembryoplasticneuroepithelial tumor, pancreatic cancer dysgerminoma pharyngeal cancerembryonal carcinoma pseudomyxoma periotonei endocrine gland neoplasmrenal cell carcinoma endodermal sinus tumor renal medullary carcinomaenteropathy-associated T-cell lymphoma retinoblastoma esophageal cancerrhabdomyoma fetus in fetu rhabdomyosarcoma fibroma Richter'stransformation fibrosarcoma rectal cancer follicular lymphoma sarcomafollicular thyroid cancer Schwannomatosis ganglioneuroma seminomagastrointestinal cancer Sertoli cell tumor germ cell tumor sexcord-gonadal stromal tumor gestational choriocarcinoma signet ring cellcarcinoma giant cell fibroblastoma skin cancer giant cell tumor of thebone small blue round cell tumors glial tumor small cell carcinomaglioblastoma multiforme soft tissue sarcoma glioma somatostatinomagliomatosis cerebri soot wart glucagonoma spinal tumor gonadoblastomasplenic marginal zone lymphoma granulosa cell tumor squamous cellcarcinoma gynandroblastoma synovial sarcoma gallbladder cancer Sezary'sdisease gastric cancer small intestine cancer hairy cell leukemiasquamous carcinoma hemangioblastoma stomach cancer head and neck cancerT-cell lymphoma hemangiopericytoma testicular cancer hematologicalmalignancy thecoma hepatoblastoma thyroid cancer hepatosplenic T-celllymphoma transitional cell carcinoma Hodgkin's lymphoma throat cancernon-Hodgkin's lymphoma urachal cancer invasive lobular carcinomaurogenital cancer intestinal cancer urothelial carcinoma kidney canceruveal melanoma laryngeal cancer uterine cancer lentigo maligna verrucouscarcinoma lethal midline carcinoma visual pathway glioma leukemia vulvarcancer leydig cell tumor vaginal cancer liposarcoma Waldenstrom'smacroglobulinemia lung cancer Warthin's tumor lymphangioma Wilms' tumorlymphangiosarcoma

In another embodiment, the cancer is a leukemia, for example a leukemiaselected from acute monocytic leukemia, acute myelogenous leukemia,chronic myelogenous leukemia, chronic lymphocytic leukemia and mixedlineage leukemia (MLL). In another embodiment the cancer is NUT-midlinecarcinoma. In another embodiment the cancer is multiple myeloma. Inanother embodiment the cancer is a lung cancer such as small cell lungcancer (SCLC). In another embodiment the cancer is a neuroblastoma. Inanother embodiment the cancer is Burkitt's lymphoma. In anotherembodiment the cancer is cervical cancer. In another embodiment thecancer is esophageal cancer. In another embodiment the cancer is ovariancancer. In another embodiment the cancer is colorectal cancer. Inanother embodiment, the cancer is prostate cancer. In anotherembodiment, the cancer is breast cancer.

In another embodiment, the cancer is anaplastic large-cell lymphoma,non-small cell lung cancer, diffuse large B-cell lymphoma, inflammatorymyofibroblastic tumors, neuroblastoma, anaplastic thyroid cancer, andrhabdomyosarcoma.

In another embodiment, the cancer is breast cancer, colorectal cancer,esophageal squamous cell cancer, and renal cell carcinoma.

In another embodiment, the present disclosure provides a method oftreating a benign proliferative disorder, such as, but are not limitedto, benign soft tissue tumors, bone tumors, brain and spinal tumors,eyelid and orbital tumors, granuloma, lipoma, meningioma, multipleendocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma,pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroidnodules, cystic neoplasms of the pancreas, hemangiomas, vocal cordnodules, polyps, and cysts, Castleman disease, chronic pilonidaldisease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenilepolyposis syndrome.

Compounds of the Disclosure can also treat infectious and noninfectiousinflammatory events and autoimmune and other inflammatory diseases byadministration of an effective amount of a present compound to a mammal,in particular a human in need of such treatment. Examples of autoimmuneand inflammatory diseases, disorders, and syndromes treated using thecompounds and methods described herein include inflammatory pelvicdisease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis,meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis,gastritis, enteritis, dermatitis, gingivitis, appendictitis,pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy,Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren'sdisease, tissue graft rejection, hyperacute rejection of transplantedorgans, asthma, allergic rhinitis, chronic obstructive pulmonary disease(COPD), autoimmune polyglandular disease (also known as autoimmunepolyglandular syndrome), autoimmune alopecia, pernicious anemia,glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma,vasculitis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson'sdisease, Alzheimer's disease, Type I diabetes, septic shock, systemiclupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis,juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenicpurpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituatarism, Guillain-Barre syndrome, Behcet's disease,scleracierma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease.

In another embodiment, the present disclosure provides a method oftreating systemic inflammatory response syndromes, such as LPS-inducedendotoxic shock and/or bacteria-induced sepsis by administration of aneffective amount of a Compound of the Disclosure to a mammal, inparticular a human in need of such treatment.

In another embodiment, the present disclosure provides a method fortreating viral infections and diseases. Examples of viral infections anddiseases treated using the compounds and methods described hereininclude episome-based DNA viruses including, but not limited to, humanpapillomavirus, Herpesvirus, Epstein-Barr virus, human immunodeficiencyvirus, hepatis B virus, and hepatitis C virus.

In another embodiment, the present disclosure provides therapeuticmethod of modulating protein methylation, gene expression, cellproliferation, cell differentiation and/or apoptosis in vivo in diseasesmentioned above, in particular cancer, inflammatory disease, and/orviral disease is provided by administering a therapeutically effectiveamount of a Compound of the Disclosure to a subject in need of suchtherapy.

In another embodiment, the present disclosure provides a method ofregulating endogenous or heterologous promoter activity by contacting acell with a Compound of the Disclosure.

In methods of the present disclosure, a therapeutically effective amountof a Compound of the Disclosure, typically formulated in accordance withpharmaceutical practice, is administered to a human being in needthereof. Whether such a treatment is indicated depends on the individualcase and is subject to medical assessment (diagnosis) that takes intoconsideration signs, symptoms, and/or malfunctions that are present, therisks of developing particular signs, symptoms and/or malfunctions, andother factors.

A Compound of the Disclosure can be administered by any suitable route,for example by oral, buccal, inhalation, sublingual, rectal, vaginal,intracisternal or intrathecal through lumbar puncture, transurethral,nasal, percutaneous, i.e., transdermal, or parenteral (includingintravenous, intramuscular, subcutaneous, intracoronary, intradermal,intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar,intrapulmonary injection and/or surgical implantation at a particularsite) administration. Parenteral administration can be accomplishedusing a needle and syringe or using a high pressure technique.

Pharmaceutical compositions include those wherein a Compound of theDisclosure is administered in an effective amount to achieve itsintended purpose. The exact formulation, route of administration, anddosage is determined by an individual physician in view of the diagnosedcondition or disease. Dosage amount and interval can be adjustedindividually to provide levels of a Compound of the Disclosure that issufficient to maintain therapeutic effects.

Toxicity and therapeutic efficacy of the Compounds of the Disclosure canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the maximum tolerated dose(MTD) of a compound, which defines as the highest dose that causes notoxicity in animals. The dose ratio between the maximum tolerated doseand therapeutic effects (e.g. inhibiting of tumor growth) is thetherapeutic index. The dosage can vary within this range depending uponthe dosage form employed, and the route of administration utilized.Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

A therapeutically effective amount of a Compound of the Disclosurerequired for use in therapy varies with the nature of the conditionbeing treated, the length of time that activity is desired, and the ageand the condition of the patient, and ultimately is determined by theattendant physician. Dosage amounts and intervals can be adjustedindividually to provide plasma levels of the ALK inhibitor that aresufficient to maintain the desired therapeutic effects. The desired doseconveniently can be administered in a single dose, or as multiple dosesadministered at appropriate intervals, for example as one, two, three,four or more subdoses per day. Multiple doses often are desired, orrequired. For example, a Compound of the Disclosure can be administeredat a frequency of: four doses delivered as one dose per day at four-dayintervals (q4d×4); four doses delivered as one dose per day at three-dayintervals (q3d×4); one dose delivered per day at five-day intervals(qd×5); one dose per week for three weeks (qwk3); five daily doses, withtwo days rest, and another five daily doses (5/2/5); or, any doseregimen determined to be appropriate for the circumstance.

A Compound of the Disclosure used in a method of the present disclosurecan be administered in an amount of about 0.005 to about 500 milligramsper dose, about 0.05 to about 250 milligrams per dose, or about 0.5 toabout 100 milligrams per dose. For example, a Compound of the Disclosurecan be administered, per dose, in an amount of about 0.005, 0.05, 0.5,5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500milligrams, including all doses between 0.005 and 500 milligrams.

The dosage of a composition containing a Compound of the Disclosure, ora composition containing the same, can be from about 1 ng/kg to about200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about50 mg/kg. The dosage of a composition can be at any dosage including,but not limited to, about 1 μg/kg. The dosage of a composition may be atany dosage including, but not limited to, about 1 μg/kg, about 10 μg/kg,about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925μg/kg, about 950 μg/kg, about 975 μg/kg, about 1 mg/kg, about 5 mg/kg,about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg,about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200mg/kg, or more. The above dosages are exemplary of the average case, butthere can be individual instances in which higher or lower dosages aremerited, and such are within the scope of this disclosure. In practice,the physician determines the actual dosing regimen that is most suitablefor an individual patient, which can vary with the age, weight, andresponse of the particular patient.

As stated above, a Compound of the Disclosure can be administered incombination with a second therapeutically active agent. In someembodiments, the second therapeutic agent is an epigenetic drug. As usedherein, the term “epigenetic drug” refers to a therapeutic agent thattargets an epigenetic regulator. Examples of epigenetic regulatorsinclude the histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histoneacetylases, and DNA methyltransferases. Histone deacetylase inhibitorsinclude, but are not limited to, vorinostat.

In another embodiment, chemotherapeutic agents or otheranti-proliferative agents can be combined with Compound of theDisclosure to treat proliferative diseases and cancer. Examples oftherapies and anticancer agents that can be used in combination withCompounds of the Disclosure include surgery, radiotherapy (e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and systemic radioactive isotopes),endocrine therapy, a biologic response modifier (e.g., an interferon, aninterleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy,an agent to attenuate any adverse effect (e.g., an antiemetic), and anyother approved chemotherapeutic drug.

Examples of antiproliferative compounds include, but are not limited to,an aromatase inhibitor; an anti-estrogen; an anti-androgen; agonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase IIinhibitor; a microtubule active agent; an alkylating agent; a retinoid,a carontenoid, or a tocopherol; a cyclooxygenase inhibitor; an MMPinhibitor; an mTOR inhibitor; an antimetabolite; a platin compound; amethionine aminopeptidase inhibitor; a bisphosphonate; anantiproliferative antibody; a heparanase inhibitor; an inhibitor of Rasoncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; acompound used in the treatment of hematologic malignancies; a Flt-3inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor; aMEK inhibitor; an antitumor antibiotic; a nitrosourea; a compoundtargeting/decreasing protein or lipid kinase activity, a compoundtargeting/decreasing protein or lipid phosphatase activity, or anyfurther anti-angiogenic compound.

Nonlimiting exemplary aromatase inhibitors include, but are not limitedto, steroids, such as atamestane, exemestane, and formestane, andnon-steroids, such as aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole, and letrozole.

Nonlimiting anti-estrogens include, but are not limited to, tamoxifen,fulvestrant, raloxifene, and raloxifene hydrochloride. Anti-androgensinclude, but are not limited to, bicalutamide. Gonadorelin agonistsinclude, but are not limited to, abarelix, goserelin, and goserelinacetate.

Exemplary topoisomerase I inhibitors include, but are not limited to,topotecan, gimatecan, irinotecan, camptothecin and its analogues,9-nitrocamptothecin, and the macromolecular camptothecin conjugatePNU-166148. Topoisomerase II inhibitors include, but are not limited to,anthracyclines, such as doxorubicin, daunorubicin, epirubicin,idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone andlosoxantrone; and podophillotoxines, such as etoposide and teniposide.

Microtubule active agents include microtubule stabilizing, microtubuledestabilizing compounds, and microtubulin polymerization inhibitorsincluding, but not limited to, taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate,vincristine, and vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof.

Exemplary nonlimiting alkylating agents include cyclophosphamide,ifosfamide, melphalan, and nitrosoureas, such as carmustine andlomustine.

Exemplary nonlimiting cyclooxygenase inhibitors include Cox-2inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid andderivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or a5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib.

Exemplary nonlimiting matrix metalloproteinase inhibitors (“MMPinhibitors”) include collagen peptidomimetic and nonpeptidomimeticinhibitors, tetracycline derivatives, batimastat, marimastat,prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, andAAJ996.

Exemplary nonlimiting mTOR inhibitors include compounds that inhibit themammalian target of rapamycin (mTOR) and possess antiproliferativeactivity such as sirolimus, everolimus, CCI-779, and ABT578.

Exemplary nonlimiting antimetabolites include 5-fluorouracil (5-FU),capecitabine, gemcitabine, DNA demethylating compounds, such as5-azacytidine and decitabine, methotrexate and edatrexate, and folicacid antagonists, such as pemetrexed.

Exemplary nonlimiting platin compounds include carboplatin, cis-platin,cisplatinum, and oxaliplatin.

Exemplary nonlimiting methionine aminopeptidase inhibitors includebengamide or a derivative thereof and PPI-2458.

Exemplary nonlimiting bisphosphonates include etridonic acid, clodronicacid, tiludronic acid, pamidronic acid, alendronic acid, ibandronicacid, risedronic acid, and zoledronic acid.

Exemplary nonlimiting antiproliferative antibodies include trastuzumab,trastuzumab-DM1, cetuximab, bevacizumab, rituximab, PR064553, and 2C4.The term “antibody” includes intact monoclonal antibodies, polyclonalantibodies, multi specific antibodies formed from at least two intactantibodies, and antibody fragments, so long as they exhibit the desiredbiological activity.

Exemplary nonlimiting heparanase inhibitors include compounds thattarget, decrease, or inhibit heparin sulfate degradation, such as PI-88and OGT2115.

The term “an inhibitor of Ras oncogenic isoforms,” such as H-Ras, K-Ras,or N-Ras, as used herein refers to a compound which targets, decreases,or inhibits the oncogenic activity of Ras, for example, a farnesyltransferase inhibitor, such as L-744832, DK8G557, tipifarnib, andlonafarnib.

Exemplary nonlimiting telomerase inhibitors include compounds thattarget, decrease, or inhibit the activity of telomerase, such ascompounds that inhibit the telomerase receptor, such as telomestatin.

Exemplary nonlimiting proteasome inhibitors include compounds thattarget, decrease, or inhibit the activity of the proteasome including,but not limited to, bortezomid.

The phrase “compounds used in the treatment of hematologic malignancies”as used herein includes FMS-like tyrosine kinase inhibitors, which arecompounds targeting, decreasing or inhibiting the activity of FMS-liketyrosine kinase receptors (Flt-3R); interferon,I-β-D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors,which are compounds which target, decrease, or inhibit anaplasticlymphoma kinase.

Exemplary nonlimiting Flt-3 inhibitors include PKC412, midostaurin, astaurosporine derivative, SU11248, and MLN518.

Exemplary nonlimiting HSP90 inhibitors include compounds targeting,decreasing, or inhibiting the intrinsic ATPase activity of HSP90; ordegrading, targeting, decreasing or inhibiting the HSP90 client proteinsvia the ubiquitin proteosome pathway. Compounds targeting, decreasing orinhibiting the intrinsic ATPase activity of HSP90 are especiallycompounds, proteins, or antibodies that inhibit the ATPase activity ofHSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), ageldanamycin derivative; other geldanamycin related compounds; radicicoland HDAC inhibitors.

The phrase “a compound targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or any furtheranti-angiogenic compound” as used herein includes a protein tyrosinekinase and/or serine and/or threonine kinase inhibitor or lipid kinaseinhibitor, such as a) a compound targeting, decreasing, or inhibitingthe activity of the platelet-derived growth factor-receptors (PDGFR),such as a compound that targets, decreases, or inhibits the activity ofPDGFR, such as an N-phenyl-2-pyrimidine-amine derivatives, such asimatinib, SU1O1, SU6668, and GFB-111; b) a compound targeting,decreasing, or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) a compound targeting, decreasing, orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as a compound that targets, decreases, or inhibits theactivity of IGF-IR; d) a compound targeting, decreasing, or inhibitingthe activity of the Trk receptor tyrosine kinase family, or ephrin B4inhibitors; e) a compound targeting, decreasing, or inhibiting theactivity of the Axl receptor tyrosine kinase family; f) a compoundtargeting, decreasing, or inhibiting the activity of the Ret receptortyrosine kinase; g) a compound targeting, decreasing, or inhibiting theactivity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h)a compound targeting, decreasing, or inhibiting the activity of thec-Kit receptor tyrosine kinases, such as imatinib; i) a compoundtargeting, decreasing, or inhibiting the activity of members of thec-Abl family, their gene-fusion products (e.g. Bcr-Abl kinase) andmutants, such as an N-phenyl-2-pyrimidine-amine derivative, such asimatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; ordasatinib; j) a compound targeting, decreasing, or inhibiting theactivity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1,PKB/Akt, and Ras/MAPK family members, and/or members of thecyclin-dependent kinase family (CDK), such as a staurosporine derivativedisclosed in U.S. Pat. No. 5,093,330, such as midostaurin; examples offurther compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1,perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; a isochinoline compound; a farnesyl transferaseinhibitor; PD184352 or QAN697, or AT7519; k) a compound targeting,decreasing or inhibiting the activity of a protein-tyrosine kinase, suchas imatinib mesylate or a tyrphostin, such as Tyrphostin A23/RG-50810;AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490;Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) a compound targeting, decreasing, orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180;trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, C1-1033, EKB-569,GW-2016, antibodies E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 andE7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and m) a compoundtargeting, decreasing, or inhibiting the activity of the c-Met receptor.

Exemplary compounds that target, decrease, or inhibit the activity of aprotein or lipid phosphatase include inhibitors of phosphatase 1,phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity unrelated to protein or lipid kinaseinhibition, e.g., thalidomide and TNP-470.

Additional, nonlimiting, exemplary chemotherapeutic compounds, one ormore of which may be used in combination with a present ALK inhibitorinclude: daunorubicin, adriamycin, Ara-C, VP-16, teniposide,mitoxantrone, idarubicin, carboplatinum, PKC412, 6-mercaptopurine(6-MP), fludarabine phosphate, octreotide, SOM230, FTY720,6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea,2-hydroxy-1H-isoindole-1,3-dione derivatives,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate,angiostatin, endostatin, anthranilic acid amides, ZD4190, ZD6474,SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitors,FLT-3 inhibitors, VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimersodium, anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol,cortex olone, 17a-hydroxyprogesterone, corticosterone,desoxycorticosterone, testosterone, estrone, dexamethasone,fluocinolone, a plant alkaloid, a hormonal compound and/or antagonist, abiological response modifier, such as a lymphokine or interferon, anantisense oligonucleotide or oligonucleotide derivative, shRNA, andsiRNA.

Other examples of second therapeutic agents, one or more of which apresent ALK inhibitor also can be combined, include, but are not limitedto: a treatment for Alzheimer's Disease, such as donepezil andrivastigmine; a treatment for Parkinson's Disease, such asL-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine,pergolide, trihexephendyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., AVONEX® andREBIF®), glatiramer acetate, and mitoxantrone; a treatment for asthma,such as albuterol and montelukast; an agent for treating schizophrenia,such as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent, such as a corticosteroid, a TNF blocker, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; animmunomodulatory agent, including immunosuppressive agents, such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, aninterferon, a corticosteroid, cyclophosphamide, azathioprine, andsulfasalazine; a neurotrophic factor, such as an acetylcholinesteraseinhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ionchannel blocker, riluzole, or an anti-Parkinson's agent; an agent fortreating cardiovascular disease, such as a beta-blocker, an ACEinhibitor, a diuretic, a nitrate, a calcium channel blocker, or astatin; an agent for treating liver disease, such as a corticosteroid,cholestyramine, an interferon, and an anti-viral agent; an agent fortreating blood disorders, such as a corticosteroid, an anti-leukemicagent, or a growth factor; or an agent for treating immunodeficiencydisorders, such as gamma globulin.

The above-mentioned second therapeutically active agents, one or more ofwhich can be used in combination with a Compound of the Disclosure, areprepared and administered as described in the art.

Compounds of the Disclosure typically are administered in admixture witha pharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. Pharmaceuticalcompositions for use in accordance with the present disclosure areformulated in a conventional manner using one or more physiologicallyacceptable carriers comprising excipients and/or auxiliaries thatfacilitate processing of Compound of the Disclosure.

These pharmaceutical compositions can be manufactured, for example, byconventional mixing, dissolving, granulating, dragee-making,emulsifying, encapsulating, entrapping, or lyophilizing processes.Proper formulation is dependent upon the route of administration chosen.When a therapeutically effective amount of the Compound of theDisclosure is administered orally, the composition typically is in theform of a tablet, capsule, powder, solution, or elixir. Whenadministered in tablet form, the composition additionally can contain asolid carrier, such as a gelatin or an adjuvant. The tablet, capsule,and powder contain about 0.01% to about 95%, and preferably from about1% to about 50%, of a Compound of the Disclosure. When administered inliquid form, a liquid carrier, such as water, petroleum, or oils ofanimal or plant origin, can be added. The liquid form of the compositioncan further contain physiological saline solution, dextrose or othersaccharide solutions, or glycols. When administered in liquid form, thecomposition contains about 0.1% to about 90%, and preferably about 1% toabout 50%, by weight, of a Compound of the Disclosure.

When a therapeutically effective amount of a Compound of the Disclosureis administered by intravenous, cutaneous, or subcutaneous injection,the composition is in the form of a pyrogen-free, parenterallyacceptable aqueous solution. The preparation of such parenterallyacceptable solutions, having due regard to pH, isotonicity, stability,and the like, is within the skill in the art. A preferred compositionfor intravenous, cutaneous, or subcutaneous injection typicallycontains, an isotonic vehicle.

Compounds of the Disclosure can be readily combined withpharmaceutically acceptable carriers well-known in the art. In oneembodiment, a pharmaceutical composition comprising a Compound of theDisclosure, or a pharmaceutically acceptable salt or hydrate thereof,and a pharmaceutically acceptable carrier, is provided. Standardpharmaceutical carriers are described in Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., 19th ed. 1995. Such carriersenable the active agents to be formulated as tablets, pills, dragees,capsules, liquids, gels, syrups, slurries, suspensions and the like, fororal ingestion by a patient to be treated. Pharmaceutical preparationsfor oral use can be obtained by adding the Compound of the Disclosure toa solid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipientsinclude, for example, fillers and cellulose preparations. If desired,disintegrating agents can be added.

Compound of the Disclosure can be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection can be presented in unit dosageform, e.g., in ampules or in multidose containers, with an addedpreservative. The compositions can take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing, and/or dispersingagents.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of the active agent in water-soluble form.Additionally, suspensions of a Compound of the Disclosure can beprepared as appropriate oily injection suspensions. Suitable lipophilicsolvents or vehicles include fatty oils or synthetic fatty acid esters.Aqueous injection suspensions can contain substances which increase theviscosity of the suspension. Optionally, the suspension also can containsuitable stabilizers or agents that increase the solubility of thecompounds and allow for the preparation of highly concentratedsolutions. Alternatively, a present composition can be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

Compounds of the Disclosure also can be formulated in rectalcompositions, such as suppositories or retention enemas, e.g.,containing conventional suppository bases. In addition to theformulations described previously, the Compound of the Disclosure alsocan be formulated as a depot preparation. Such long-acting formulationscan be administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, theCompound of the Disclosure can be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion exchange resins.

In particular, the Compounds of the Disclosure can be administeredorally, buccally, or sublingually in the form of tablets containingexcipients, such as starch or lactose, or in capsules or ovules, eitheralone or in admixture with excipients, or in the form of elixirs orsuspensions containing flavoring or coloring agents. Such liquidpreparations can be prepared with pharmaceutically acceptable additives,such as suspending agents. Compound of the Disclosure also can beinjected parenterally, for example, intravenously, intramuscularly,subcutaneously, or intracoronarily. For parenteral administration, theCompound of the Disclosure are typically used in the form of a sterileaqueous solution which can contain other substances, for example, saltsor monosaccharides, such as mannitol or glucose, to make the solutionisotonic with blood.

In another embodiment, the present disclosure provides kits whichcomprise a Compound of the Disclosure (or a composition comprising aCompound of the Disclosure) packaged in a manner that facilitates theiruse to practice methods of the present disclosure. In one embodiment,the kit includes a Compound of the Disclosure (or a compositioncomprising a Compound of the Disclosure) packaged in a container, suchas a sealed bottle or vessel, with a label affixed to the container orincluded in the kit that describes use of the compound or composition topractice the method of the disclosure. In one embodiment, the compoundor composition is packaged in a unit dosage form. The kit further caninclude a device suitable for administering the composition according tothe intended route of administration.

The term “a disease or condition wherein inhibition of ALK provides abenefit” pertains to a disease or condition in which ALK, is importantor necessary, e.g., for the onset, progress, expression of that diseaseor condition, or a disease or a condition which is known to be treatedby an ALK inhibitor. Examples of such conditions include, but are notlimited to, a cancer, a chronic autoimmune disease, an inflammatorydisease, a proliferative disease, sepsis, and a viral infection. One ofordinary skill in the art is readily able to determine whether acompound treats a disease or condition mediated by an ALK inhibitor forany particular cell type, for example, by assays which conveniently canbe used to assess the activity of particular compounds. The term“anaplastic lymphoma kinase” or “ALK” includes isoforms and mutants ofALK.

The term “second therapeutic agent” refers to a therapeutic agentdifferent from a Compound of the Disclosure and that is known to treatthe disease or condition of interest. For example when a cancer is thedisease or condition of interest, the second therapeutic agent can be aknown chemotherapeutic drug, like taxol, or radiation, for example.

The term “disease” or “condition” denotes disturbances and/or anomaliesthat as a rule are regarded as being pathological conditions orfunctions, and that can manifest themselves in the form of particularsigns, symptoms, and/or malfunctions. As demonstrated below, Compoundsof the Disclosure are inhibitors of ALK and can be used in treating orpreventing diseases and conditions wherein inhibition of ALK provides abenefit.

As used herein, the terms “treat,” “treating,” “treatment,” and the likerefer to eliminating, reducing, or ameliorating a disease or condition,and/or symptoms associated therewith. Although not precluded, treating adisease or condition does not require that the disease, condition, orsymptoms associated therewith be completely eliminated. The term “treat”and synonyms contemplate administering a therapeutically effectiveamount of a Compound of the Disclosure to a subject in need of suchtreatment. The treatment can be orientated symptomatically, for example,to suppress symptoms. It can be effected over a short period, beoriented over a medium term, or can be a long-term treatment, forexample within the context of a maintenance therapy.

As used herein, the terms “prevent,” “preventing,” and “prevention”refer to a method of preventing the onset of a disease or conditionand/or its attendant symptoms or barring a subject from acquiring adisease. As used herein, “prevent,” “preventing,” and “prevention” alsoinclude delaying the onset of a disease and/or its attendant symptomsand reducing a subject's risk of acquiring a disease. The terms“prevent,” “preventing” and “prevention” may include “prophylactictreatment,” which refers to reducing the probability of redeveloping adisease or condition, or of a recurrence of a previously-controlleddisease or condition, in a subject who does not have, but is at risk ofor is susceptible to, redeveloping a disease or condition or arecurrence of the disease or condition.

The term “therapeutically effective amount” or “effective dose” as usedherein refers to an amount of the active ingredient(s) that is(are)sufficient, when administered by a method of the disclosure, toefficaciously deliver the active ingredient(s) for the treatment ofcondition or disease of interest to an individual in need thereof. Inthe case of a cancer or other proliferation disorder, thetherapeutically effective amount of the agent may reduce (i.e., retardto some extent and preferably stop) unwanted cellular proliferation;reduce the number of cancer cells; reduce the tumor size; inhibit (i.e.,retard to some extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., retard to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; and/orrelieve, to some extent, one or more of the symptoms associated with thecancer. To the extent the administered compound or composition preventsgrowth and/or kills existing cancer cells, it may be cytostatic and/orcytotoxic.

The term “container” means any receptacle and closure therefore suitablefor storing, shipping, dispensing, and/or handling a pharmaceuticalproduct.

The term “insert” means information accompanying a pharmaceuticalproduct that provides a description of how to administer the product,along with the safety and efficacy data required to allow the physician,pharmacist, and patient to make an informed decision regarding use ofthe product. The package insert generally is regarded as the “label” fora pharmaceutical product.

“Concurrent administration,” “administered in combination,”“simultaneous administration,” and similar phrases mean that two or moreagents are administered concurrently to the subject being treated. By“concurrently,” it is meant that each agent is administered eithersimultaneously or sequentially in any order at different points in time.However, if not administered simultaneously, it is meant that they areadministered to an individual in a sequence and sufficiently close intime so as to provide the desired therapeutic effect and can act inconcert. For example, a Compound of the Disclosure can be administeredat the same time or sequentially in any order at different points intime as a second therapeutic agent. A Compound of the Disclosure and thesecond therapeutic agent can be administered separately, in anyappropriate form and by any suitable route. When a Compound of theDisclosure and the second therapeutic agent are not administeredconcurrently, it is understood that they can be administered in anyorder to a subject in need thereof. For example, a Compound of theDisclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, orsubsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours,96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks,or 12 weeks after) the administration of a second therapeutic agenttreatment modality (e.g., radiotherapy), to an individual in needthereof. In various embodiments, a Compound of the Disclosure and thesecond therapeutic agent are administered 1 minute apart, 10 minutesapart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hoursapart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, nomore than 24 hours apart or no more than 48 hours apart. In oneembodiment, the components of the combination therapies are administeredat about 1 minute to about 24 hours apart.

The use of the terms “a”, “an”, “the”, and similar referents in thecontext of describing the disclosure (especially in the context of theclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated. Recitation of ranges of values herein merelyare intended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended to better illustrate the disclosure and is not a limitation onthe scope of the disclosure unless otherwise claimed. No language in thespecification should be construed as indicating any non-claimed elementas essential to the practice of the disclosure.

In the present disclosure, the term “alkyl” as used by itself or as partof another group refers to unsubstituted straight- or branched-chainaliphatic hydrocarbons containing from one to twelve carbon atoms, i.e.,C₁₋₁₂ alkyl, or the number of carbon atoms designated, e.g., a C₁ alkylsuch as methyl, a C₂ alkyl such as ethyl, a C₃ alkyl such as propyl orisopropyl, a C₁₋₃ alkyl such as methyl, ethyl, propyl, or isopropyl, andso on. In one embodiment, the alkyl is a C₁₋₄ alkyl. Non-limitingexemplary C₁₋₁₂ alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl,nonyl, and decyl. Exemplary C₁₋₄ alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

In the present disclosure, the term “cycloalkyl” as used by itself or aspart of another group refers to saturated and partially unsaturated(containing one or two double bonds) cyclic aliphatic hydrocarbonscontaining one or two rings having from three to twelve carbon atoms(i.e., C₃₋₁₂ cycloalkyl) or the number of carbons designated. In oneembodiment, the cycloalkyl group has two rings. In one embodiment, thecycloalkyl group has one ring. In another embodiment, the cycloalkylgroup is chosen from a C₃₋₈ cycloalkyl group. In another embodiment, thecycloalkyl group is chosen from a C₃₋₆ cycloalkyl group. Non-limitingexemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin,adamantyl, cyclohexenyl, cyclopentenyl, and cyclohexenyl.

In the present disclosure, the term “heterocycle” or “heterocyclo” asused by itself or as part of another group refers to saturated andpartially unsaturated (e.g., containing one or two double bonds) cyclicgroups containing one, two, or three rings having from three to fourteenring members (i.e., a 3- to 14-membered heterocyclo) wherein at leastone carbon atom of one of the rings is replaced with a heteroatom. Eachheteroatom is independently selected from the group consisting ofoxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms,which can be oxidized or quaternized. The term “heterocyclo” is meant toinclude groups wherein a ring —CH₂— is replaced with a —C(═O)—, forexample, cyclic ureido groups such as 2-imidazolidinone and cyclic amidegroups such as β-lactam, γ-lactam, δ-lactam, ε-lactam, andpiperazin-2-one. In one embodiment, the heterocyclo group is a 3- to8-membered cyclic group containing one ring and one or two oxygen and/ornitrogen atoms. In one embodiment, the heterocyclo group is a 4-, 5- or6-membered cyclic group containing one ring and one or two oxygen and/ornitrogen atoms. In one embodiment, the heterocyclo group is a 4- or6-membered cyclic group containing one ring and one oxygen or nitrogenatom. The heterocyclo can be optionally linked to the rest of themolecule through any available carbon or nitrogen atom. Non-limitingexemplary heterocyclo groups include dioxanyl, tetrahydropyranyl,2-oxopyrrolidin-3-yl, piperazin-2-one, piperazine-2,6-dione,2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl,and indolinyl.

EXAMPLES Example 1 Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step A: Synthesis of4-(5-fluoro-2-methyl-4-nitrophenyl)-2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine

2,2,6,6-Tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(1.0 g, 3.77 mmol), Pd(dppf)Cl₂ (110 mg, 0.15 mmol), and K₂CO₃ (1.56 g,11.31 mmol) were added to a solution of1-bromo-5-fluoro-2-methyl-4-nitrobenzene (883 mg, 3.77 mmol) in DME-H₂O(22 mL, 10:1 mixture). The mixture was stirred at 80° C. for 12 hr undernitrogen. The reaction was cooled to room temperature and the productwas extracted with ethyl acetate. The solvent was removed under reducedpressure and the residue was purified by silica gel chromatography withethyl acetate/methanol (9/1, v/v) to afford the title compound (0.99 g,90% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.88 (d, J=7.6 Hz, 1H), 6.97(d, J=11.6 Hz, 1H), 5.63 (s, 1H), 2.34 (s, 3H), 2.09-2.02 (m, 3H), 1.28(s, 6H), 1.26 (s, 6H).

Step B: Synthesis of4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine

To a solution of tert-Butyl4-(5-nitro-2-vinylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.99 g,3.4 mmol) in 20 mL of 2-propanol was added Cs₂CO₃ (3.32 g, 10.2 mmol).The mixture was stirred at 60° C. overnight, and after cooling to roomtemperature, most of the 2-propanol was evaporated under reducedpressure. Water was added, and the solution was extracted with ethylacetate. The organic layers were combined, dried over anhydrous Na₂SO₄,concentrated, and the crude product was purified by silica gelchromatography with ethyl acetate/methanol (9/1, v/v) to afford thetitle compound (0.9 g, 79%) as a pale yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.62 (s, 1H), 6.72 (s, 1H), 5.57 (t, J=1.7 Hz, 1H), 4.63-4.60(m, 1H), 2.26 (s, 3H), 2.10-2.20 (m, 3H), 1.38 (d, J=6.0 Hz, 6H), 1.28(s, 6H), 1.25 (s, 6H).

Step C: Synthesis of2-isopropoxy-5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

To a solution of4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine(320 mg, 0.96 mmol) in 20 mL of ethanol was added several drops of 10%HCl, followed by iron powder (322 mg, 5.76 mmol). The mixture wasstirred at 60° C. for 3 hr. The reaction was cooled to room temperatureand the iron powder was filtered off. Ethanol was removed under reducedpressure and the title compound was obtained as colorless oil (250 mg,86% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.54 (s, 1H), 6.51 (s, 1H), 5.47(s, 1H), 4.49-4.45 (m, 1H), 3.68 (s, 2H), 2.17 (s, 3H), 2.05 (s, 2H),1.34 (d, J=6.0 Hz, 6H), 1.25 (s, 6H), 1.23 (s, 6H).

Step D: Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

2-Isopropoxy-5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)aniline (250 mg, 0.828 mmol),2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl) pyrimidin-4-amine (286 mg,0.828 mmol), Xantphos (48 mg, 0.083 mmol), Pd(OAc)₂ (9.3 mg, 0.042mmol), and Cs₂CO₃ (810 mg, 2.48 mmol) were dissolved in anhydrous THF(10 mL). N₂ was bubbled through the reaction mixture for 5 min, and thenthe reaction vessel was sealed and heated under microwave irradiation to150° C. for 30 min. The mixture was filtered and the filtrateconcentrated under reduced pressure. After concentration, the crudeproduct was purified by prep-HPLC (gradient from 10% to 60% acetonitrilein water) to give the title compound (130 mg, 26% yield). ¹H NMR (400MHz, CD₃OD) δ 8.37 (dd, J=8.3, 1.1 Hz, 1H), 8.24 (s, 1H), 7.99 (dd,J=8.0, 1.6 Hz, 1H), 7.80-7.62 (m, 2H), 7.52-7.38 (m, 1H), 6.76 (s, 1H),5.62 (t, J=1.7 Hz, 1H), 4.70-4.58 (m, 1H), 3.44-3.33 (m, 1H), 2.50 (d,J=1.7 Hz, 2H), 2.14 (s, 3H), 1.63 (s, 6H), 1.59 (s, 6H), 1.34 (d, J=6.0Hz, 6H), 1.27 (d, J=6.8 Hz, 6H).

Example 2 Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step A: Synthesis of4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridine

37% Formaldehyde (365 mg, 4.5 mmol), acetic acid (135 mg, 2.25 mmol),and sodium triacetoxyborohydride (477 mg, 2.25 mmol) were added to asolution of4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine(500 mg, 1.5 mmol) in DCM (20 mL) and the mixture was stirred at roomtemperature for 12 hr. Water was added to quench the reaction and themixture was extracted with DCM. The solvent was removed under and theresidue was purified by silica gel chromatography with ethylacetate/methanol (9/1, v/v) to afford the title compound (460 mg, 88%yield) as a slightly yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.62 (s,1H), 6.76 (s, 1H), 5.42 (s, 1H), 4.65-4.56 (m, 1H), 2.38 (s, 3H), 2.28(s, 3H), 2.22 (s, 2H), 1.37 (d, J=6.1 Hz, 6H), 1.24 (s, 6H), 1.20 (s,6H).

Step B: Synthesis of2-isopropoxy-5-methyl-4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

To a solution of4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridine(460 mg, 1.33 mmol) in 20 mL of ethanol was added several drops of 10%HCl, followed by iron powder (448 mg, 8.0 mmol). The mixture was stirredat 60° C. for 3 hr. The reaction was cooled to room temperature and theiron powder was filtered off. Ethanol was removed under reduced pressureand the title compound was obtained as colorless oil (410 mg, 98%yield). MS m/z=317 [M+H]. ¹H NMR (400 MHz, CDCl₃) δ 6.53 (s, 2H), 5.32(s, 1H), 4.40-4.40 (m, 1H), 3.67 (s, 2H), 2.35 (s, 3H), 2.19 (s, 3H),2.20-2.17 (m, 2H), 1.33 (d, J=6.1 Hz, 6H), 1.20 (s, 6H), 1.17 (s, 6H).

Step C: Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

2-Isopropoxy-5-methyl-4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridin-4-yl)aniline (154 mg, 0.488 mmol),2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl) pyrimidin-4-amine (168 mg,0.488 mmol), Xantphos (28 mg, 0.0488 mmol), Pd(OAc) 2 (5.5 mg, 0.0244mmol), and Cs₂CO₃ (477 mg, 1.464 mmol) were dissolved in anhydrous THF(10 mL). N₂ was bubbled through the reaction mixture for 5 min, and thenthe reaction vessel was sealed and heated under microwave irradiation to150° C. for 30 min. The mixture was filtered and the filtrateconcentrated under reduced pressure. After concentration, the crudeproduct was purified by prep-HPLC (gradient from 10% to 60% acetonitrilein water) to give the title compound (110 mg, 36% yield). ¹H NMR (400MHz, CD₃OD) δ 8.36 (d, J=8.3 Hz, 1H), 8.25 (s, 1H), 8.00 (dd, J=7.9, 1.6Hz, 1H), 7.80-7.62 (m, 2H), 7.55-7.40 (m, 1H), 6.78 (s, 1H), 5.62 (d,J=2.5 Hz, 1H), 4.72-4.55 (m, 1H), 3.42-3.33 (m, 1H), 2.98 (s, 3H),2.95-2.82 (m, 1H), 2.44 (d, J=18.1 Hz, 1H), 2.15 (s, 3H), 1.65 (s, 3H),1.61 (s, 3H), 1.59 (s, 3H), 1.56 (s, 3H), 1.34 (dd, J=6.0, 1.8 Hz, 6H),1.27 (d, J=6.8 Hz, 6H).

Example 3 Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step A: Synthesis of tert-butyl4-(5-fluoro-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

Tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(620 mg, 2 mmol), Pd(dppf)Cl₂ (58 mg, 0.08 mmol), and K₂CO₃ (828 mg, 6mmol) were added to a solution of1-bromo-5-fluoro-2-methyl-4-nitrobenzene (470 mg, 2 mmol) in DME-H₂O (22mL, 10:1 mixture). The mixture was stirred at 80° C. for 12 hr undernitrogen. The reaction was cooled to room temperature and the productwas extracted with ethyl acetate. Solvent was removed under reducedpressure and the residue was purified by silica gel chromatography withhexane/ethyl acetate (9/1, v/v) to afford the title compound (640 mg,95% yield) as a slightly yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.89(d, J=7.5 Hz, 1H), 7.02 (d, J=11.5 Hz, 1H), 5.68 (s, 1H), 4.10-4.07 (m,2H), 3.65 (t, J=5.6 Hz, 2H), 2.39-2.32 (m, 2H), 2.33 (s, 3H), 1.52 (s,9H).

Step B: Synthesis of tert-butyl4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl4-(5-fluoro-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate(640 mg, 1.9 mmol) in 20 mL of 2-propanol was added Cs₂CO₃ (1.862 g, 5.7mmol). The mixture was stirred at 60° C. overnight, and after cooling toroom temperature, most of the 2-propanol was evaporated under reducedpressure. Water was added, and the solution was extracted with ethylacetate. The organic layers were combined, dried over anhydrous Na₂SO₄,concentrated, and the crude product was purified by silica gelchromatography with hexane/ethyl acetate (8/2, v/v) to afford the titlecompound (650 mg, 91%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.63(s, 1H), 6.79 (s, 1H), 5.62 (s, 1H), 4.65-4.62 (m, 1H), 4.4.10-4.07 (m,2H), 3.64 (t, J=5.6 Hz, 2H), 2.36-2.34 (m, 2H), 2.25 (s, 3H), 1.52 (s,9H), 1.39 (d, J=6.1 Hz, 6H).

Step C: Synthesis of4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridine

To a solution of tert-butyl4-(5-isopropoxy-2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate(217 mg, 0.576 mmol) in dichloromethane (5 mL) was added trifluoroaceticacid (1 mL) and the reaction mixture was stirred at room temperature for6 hr. The dichloromethane and trifluoroacetic acid were removed undervacuum and 100 mL of dichloromethane was added, washed with saturatedNaHCO₃ solution. The water layer was extracted with dichloromethane foradditional two times (100 mL each). The organic layers were combined,washed with brine, dried over Na₂SO₄ and evaporated. The residue wasdissolved in dichloromethane (10 mL) and tetrahydro-4H-pyran-4-one (173mg, 1.728 mmol), sodium triacetoxyborohydride (244 mg, 1.152 mmol) andacetic acid (69 mg, 1.152 mmol) were then added. The reaction wasstirred at room temperature overnight. The reaction was quenched byadding water (80 mL), and extracted with dichloromethane (3×100 mL). Theorganic layers were combined, washed with brine, dried over Na₂SO₄,concentrated and purified by silica gel column chromatography with ethylacetate/methanol (9/1, v/v) to afford the title compound (170 mg, 82%for two steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, 1H),6.83 (s, 1H), 5.62-5.59 (m, 1H), 4.58-4.56 (m, 1H), 4.11-4.01 (m, 2H),3.43-3.28 (m, 4H), 2.78 (t, J=5.6 Hz, 2H), 2.60-2.56 (m, 1H), 2.40-2.36(m, 2H), 2.23 (s, 3H), 1.86-1.82 (m, 2H), 1.69-1.65 (m, 2H), 1.35 (d,J=6.1 Hz, 6H).

Step D: Synthesis of2-isopropoxy-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)aniline

To a solution of4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridine(2.4 g, 6.66 mmol) in 30 mL of ethanol was added 4 mL of 10% HCl,followed by iron powder (2.23 g, 40 mmol). The mixture was stirred at60° C. for 3 hr. The reaction was cooled to room temperature and theiron powder was filtered off. Ethanol was removed under reduced pressureand the title compound was obtained as pale yellow oil (2.0 g, 91%yield). MS m/z=331 [M+H].

Step E: Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

2-Isopropoxy-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)aniline(330 mg, 1 mmol),2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (345 mg, 1mmol), Xantphos (58 mg, 0.1 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), andCs₂CO₃ (975 mg, 3 mmol) were dissolved in anhydrous THF (20 mL). N₂ wasbubbled through the reaction mixture for 5 min, and then the reactionvessel was sealed and heated under microwave irradiation to 150° C. for30 min. The mixture was filtered and the filtrate concentrated underreduced pressure. After concentration, the crude product was purified byprep-HPLC (gradient from 10% to 60% acetonitrile in water) to the titlecompound (125 mg, 20% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H),8.46 (d, J=8.3 Hz, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.85 (dd, J=8.3, 1.5Hz, 1H), 7.66 (t, J=8.3 Hz, 1H), 7.59 (s, 1H), 7.37 (t, J=7.6 Hz, 1H),6.73 (s, 1H), 5.57-5.50 (m, 1H), 4.58-4.54 (m, 1H), 3.96-3.87 (m, 2H),3.47-3.43 (m, 1H), 3.31 (t, J=11.1 Hz, 2H), 3.17 (d, J=3.1 Hz, 2H), 2.70(t, J=5.5 Hz, 2H), 2.29 (t, J=4.5 Hz, 2H), 2.07 (s, 3H), 1.78-1.74 (m,2H), 1.49-1.45 (m, 2H), 1.23 (d, J=6.0 Hz, 6H), 1.16 (d, J=6.8 Hz, 6H).

Example 4 Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step A: Synthesis of tert-butyl4-(4-amino-5-isopropoxy-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate(217 mg, 0.576 mmol) in 20 mL of ethanol was added several drops of 10%HCl, followed by iron powder (194 mg, 3.457 mmol). The mixture wasstirred at 60° C. for 3 hr. The reaction was cooled to room temperatureand the iron powder was filtered off. Ethanol was removed under reducedpressure and the title compound was obtained as a pale yellow oil. Thisproduct was used directly without further purification.

Step B: Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Tert-butyl4-(4-amino-5-isopropoxy-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(120 mg, 0.348 mmol), 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (120 mg, 0.348 mmol), Xantphos (28 mg, 0.048 mmol),Pd(OAc)₂ (5.5 mg, 0.024 mmol), and Cs₂CO₃ (400 mg, 1.23 mmol) weredissolved in anhydrous THF (8 mL). N₂ was bubbled through the reactionmixture for 5 min, and then the reaction vessel was sealed and heatedunder microwave irradiation to 150° C. for 30 min. The mixture wasfiltered and the filtrate concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1mL) was added and the reaction was stirred at room temperature for 6 hr.The dichloromethane and trifluoroacetic acid were removed under vacuumand 40 mL of dichloromethane was added, washed with saturated NaHCO₃solution. The water layer was extracted with dichloromethane foradditional two times (40 mL each). The organic layers were combined,washed with brine, dried over Na₂SO₄ and evaporated. The residue wasdissolved in dichloromethane (10 mL) and oxetan-3-one (75 mg, 1.04mmol), sodium triacetoxyborohydride (118 mg, 0.56 mmol) and acetic acid(34 mg, 0.56 mmol) were then added. The reaction was stirred at roomtemperature overnight. The reaction was quenched by adding water (80mL), and extracted with dichloromethane (3×40 mL). The organic layerswere combined, washed with brine, dried over Na₂SO₄. Afterconcentration, the crude product was purified by prep-HPLC (gradientfrom 10% to 60% acetonitrile in water) to give the title compound (40mg, 19% yield). ¹H NMR (400 MHz, CD₃OD) δ ppm 8.38 (d, J=8.0 Hz, 1H),8.23 (s, 1H), 8.00-7.98 (m, 1H), 7.78-7.69 (m, 2H), 7.48-7.44 (m, 1H),6.82 (s, 1H), 5.69-5.62 (m, 1H), 5.02-4.90 (m, 4H), 4.70-4.55 (m, 2H),4.00-3.80 (m, 2H), 3.65-3.40 (m, 2H), 3.42-3.35 (m, 1H), 2.74 (s, 2H),2.14 (s, 3H), 1.34 (d, J=6.1 Hz, 6H), 1.27 (d, J=6.8 Hz, 6H).

Example 5 Synthesis of5-chloro-N²-(4-((cis)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step A: Synthesis of cis-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one

To a solution of acetone dicarboxylic acid (4 g, 27.4 mmol) in water (20mL) was added 40% acetaldehyde (6 g, 54.8 mmol). Then4-methoxyphenylmethanamine (3.75 g, 27.4 mmol) was added in smallportions over 10 min. The resulting yellow solution was stirred at roomtemperature for three days. The reaction mixture was extracted withdichloromethane (3×60 mL). Combined extracts were washed with brine anddried with anhydrous Na₂SO₄. The solution was filtered and evaporated togive brown residue. The isomeric piperidones were separated by silicagel chromatography with dichloromethane/ethyl acetate (9/1, v/v). Thedesired title compound (4.0 g, 59%) was obtained as a pale yellow oil.¹H NMR (400 MHz, CDCl₃) δ 7.30 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz,2H), 3.86 (d, J=13.7 Hz, 1H), 3.81 (s, 3H), 3.55 (d, J=13.7 Hz, 1H),3.28-3.24 (m, 2H), 2.49-2.45 (m, 2H), 2.20-2.16 (m, 2H), 1.09 (d, J=6.6Hz, 6H).

Step B: Synthesis of cis-2,6-dimethylpiperidin-4-one

Cis-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one (4.0 g, 16.2 mmol)was dissolved in ethanol (20 mL) and catalyst (0.4 g, 10% Pd—C) wasadded. The mixture was stirred under hydrogen atmosphere for 12 hr. Thecatalyst was removed by filtration and the filtrate was evaporated underreduced pressure to give the title compound (1.8 g, 88% yield). ¹H NMR(400 MHz, CDCl₃) δ 3.58-3.50 (m, 2H), 2.50-2.48 (m, 2H), 2.20-2.11 (m,2H), 1.17 (d, J=6.6 Hz, 6H).

Step C: tert-butyl-cis-2,6-dimethyl-4-oxopiperidine-1-carboxylate

Di-tert-butyl dicarbonate (3.14 g, 14.4 mmol) andN,N-diisopropylethylamine (3.1 g, 24 mmol) were added to a solution ofcis-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one (1.54 g, 12 mmol) indichloromethane (30 mL) and the mixture was stirred at room temperaturefor 12 hr. Solvent was removed under reduced pressure and the residuewas purified by silica gel chromatography with hexane/ethyl acetate(8/2, v/v) to afford the title compound (2.0 g, 73% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 4.41-4.39 (m, 2H), 2.85 (dd, J=17.8,6.5 Hz, 2H), 2.37 (dd, J=17.8, 1.9 Hz, 2H), 1.50 (s, 9H), 1.25 (d, J=6.8Hz, 6H).

Step D: Synthesis oftert-butyl-cis-2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution oftert-butyl-cis-2,6-dimethyl-4-oxopiperidine-1-carboxylate (500 mg, 2.2mmol) in THF (20 mL) was slowly added 2.0 M LDA (1.1 mL, 2.2 mmol) inTHF at −78° C. After 20 min, a solution of1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(786 mg, 2.2 mmol) was slowly added to the mixture. The reaction mixturewas stirred at 0° C. for 3 h. The solvent was evaporated under reducedpressure, and the residue was purified by column chromatography withhexane/ethyl acetate (20/1, v/v) to obtain the title compound (600 mg,76% yield). ¹H NMR (400 MHz, CDCl₃) δ 5.78-5.70 (m, 1H), 4.45-4.30 (m,2H), 2.85-2.78 (m, 1H), 2.25-2.15 (m, 1H), 1.48 (s, 9H), 1.37 (d, J=6.3Hz, 3H), 1.24 (d, J=6.5 Hz, 3H).

Step E: Synthesis oftert-butyl-cis-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

The suspension oftert-butyl-cis-2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(600 mg, 1.67 mmol), bis(pinacolato)diboron (467 mg, 1.84 mmol),potassium acetate (490 mg, 5.01 mmol),1,10-bis(diphenylphosphino)ferrocene (47 mg, 0.084 mmol), and[1,10-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex indichloromethane (61 mg, 0.084 mmol) were stirred in 1,4-dioxane (10 mL)at 80° C. for 12 h. The reaction mixture was extracted with ethylacetate, and the organic layer was washed with brine, dried overanhydrous Na₂SO₄, and filtered. The solvent was evaporated under reducedpressure, and the residue was purified by column chromatography withhexane/ethyl acetate (9/1, v/v) to obtain the title compound (500 mg,89% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.61-6.57 (m, 1H), 4.21-4.17 (m,2H), 2.44-2.33 (m, 1H), 2.22-2.13 (m, 1H), 1.48 (s, 9H), 1.30-1.20 (m,15H), 1.05 (d, J=6.4 Hz, 3H).

Step F: Synthesis oftert-butyl-cis-4-(5-fluoro-2-methyl-4-nitrophenyl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate

Tert-butyl-cis-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(500 mg, 1.48 mmol), Pd(dppf)Cl₂ (43 mg, 0.06 mmol), and K₂CO₃ (613 mg,4.44 mmol) were added to a solution of1-bromo-5-fluoro-2-methyl-4-nitrobenzene (417 mg, 1.78 mmol) in DME-H₂O(22 mL, 10:1 mixture). The mixture was stirred at 80° C. for 12 hr undernitrogen. The reaction was cooled to room temperature and the productwas extracted with ethyl acetate. Solvent was removed under reducedpressure and the residue was purified by silica gel chromatography withhexane/ethyl acetate (9/1, v/v) to afford the title compound (420 mg,78% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J=7.5 Hz, 1H), 7.00 (d,J=11.5 Hz, 1H), 5.87-5.84 (m, 1H), 4.44-4.32 (m, 2H), 2.94-2.84 (m, 1H),2.35 (s, 3H), 2.11-2.02 (m, 1H), 1.51 (s, 9H), 1.38 (d, J=6.4 Hz, 3H),1.21 (d, J=6.4 Hz, 3H).

Step G: Synthesis oftert-butyl-cis-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate

To a solution oftert-butyl-cis-4-(5-fluoro-2-methyl-4-nitrophenyl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate(420 mg, 1.15 mmol) in 20 mL of 2-propanol was added Cs₂CO₃ (1.128 g,3.46 mmol). The mixture was stirred at 60° C. overnight, and aftercooling to room temperature, most of the 2-propanol was evaporated underreduced pressure. Water was added, and the solution was extracted withethyl acetate. The organic layers were combined, dried over Na₂SO₄,concentrated, and the crude product was purified by silica gelchromatography with hexane/ethyl acetate (9/1, v/v) to afford the titlecompound (450 mg, 97%) as a slightly yellow oil. ¹H NMR (400 MHz, CDCl₃)δ 7.63 (s, 1H), 6.77 (s, 1H), 5.82-5.79 (m, 1H), 4.63-4.60 (m, 1H),4.38-4.34 (m, 2H), 2.92-2.87 (m, 1H), 2.27 (s, 3H), 2.11-2.00 (m, 1H),1.51 (s, 9H), 1.39-1.36 (m, 9H), 1.21 (d, J=6.3 Hz, 3H).

Step H: Synthesis oftert-butyl-cis-4-(4-amino-5-isopropoxy-2-methylphenyl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate

To a solution oftert-butyl-cis-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate(230 mg, 0.569 mmol) in 20 mL of ethanol was added several drops of 10%HCl, followed by iron powder (191 mg, 3.42 mmol). The mixture wasstirred at 60° C. for 3 hr. The reaction was cooled to room temperatureand the iron powder was filtered off. Ethanol was removed under reducedpressure and the title compound was obtained as pale yellow oil. Thisproduct was used directly without further purification.

Step I: Synthesis of5-chloro-N²-(4-(cis-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Tert-butyl-cis-4-(4-amino-5-isopropoxy-2-methylphenyl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate(213 mg, 0.57 mmol),2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (197 mg,0.57 mmol), Xantphos (33 mg, 0.057 mmol), Pd(OAc)₂ (6 mg, 0.029 mmol),and Cs₂CO₃ (555 mg, 1.71 mmol) were dissolved in anhydrous THF (20 mL).N₂ was bubbled through the reaction mixture for 5 min, and then thereaction vessel was sealed and heated under microwave irradiation to150° C. for 30 min. The mixture was filtered and the filtrateconcentrated under reduced pressure. The residue was dissolved indichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added and thereaction was stirred at room temperature for 6 hr. The dichloromethaneand trifluoroacetic acid were removed under vacuum. The residue waspurified by prep-HPLC (gradient from 10% to 60% acetonitrile in water)to give the title compound (110 mg, 33% yield). ¹H NMR (400 MHz, CD₃OD)δ 8.35 (d, J=8.3 Hz, 1H), 8.24 (s, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.74 (t,J=7.7 Hz, 1H), 7.64 (s, 1H), 7.49 (t, J=7.7 Hz, 1H), 6.80 (s, 1H),5.65-5.59 (m, 1H), 4.65-4.61 (m, 1H), 4.21-4.17 (m, 1H), 3.82-3.78 (m,1H), 3.41-3.37 (m, 1H), 2.70-2.60 (m, 1H), 2.40-2.36 (m, 1H), 2.12 (s,3H), 1.54 (d, J=6.9 Hz, 3H), 1.49 (d, J=6.5 Hz, 3H), 1.33 (d, J=6.0 Hz,6H), 1.26 (d, J=6.8 Hz, 6H).

Example 6 Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-((cis)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step A: Synthesis ofcis-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridine

To a solution oftert-butyl-cis-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate(230 mg, 0.57 mmol) in dichloromethane (5 mL) was added trifluoroaceticacid (1 mL) and the reaction mixture was stirred at room temperature for6 hr. The dichloromethane and trifluoroacetic acid were removed undervacuum and 100 mL of dichloromethane was added, washed with saturatedNaHCO₃ solution. The water layer was extracted with dichloromethane foradditional two times (100 mL each). The organic layers were combined,washed with brine, dried over Na₂SO₄ and evaporated. The residue wasdissolved in dichloromethane (10 mL) and 37% formaldehyde (138 mg, 1.71mmol), sodium triacetoxyborohydride (181 mg, 0.855 mmol) and acetic acid(51 mg, 0.855 mmol) were then added. The reaction was stirred at roomtemperature overnight. The reaction was quenched by adding water (80mL), and extracted with dichloromethane (3×100 mL). The organic layerswere combined, washed with brine, dried over Na₂SO₄, concentrated andpurified by silica gel column chromatography with ethyl acetate/methanol(9/1, v/v) to afford the title compound (190 mg, 91% for two steps) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 6.79 (s, 1H),5.50-5.46 (m, 1H), 4.60-4.56 (m, 1H), 3.27-3.09 (m, 2H), 2.55-2.51 (m,1H), 2.43 (s, 3H), 2.25 (s, 3H), 2.01-1.97 (m, 1H), 1.36 (dd, J=6.0, 2.2Hz, 6H), 1.21 (d, J=6.7 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H).

Step B: Synthesis of2-isopropoxy-5-methyl-4-(cis-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

To a solution ofcis-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridine(181 mg, 0.57 mmol) in 20 mL of ethanol was added several drops of 10%HCl, followed by iron powder (191 mg, 3.42 mmol). The mixture wasstirred at 60° C. for 3 hr. The reaction was cooled to room temperatureand the iron powder was filtered off. Ethanol was removed under reducedpressure and the title compound was obtained as yellow oil. This productwas used directly without further purification.

Step C: Synthesis of5-chloro-N²-(2-isopropoxy-5-methyl-4-(cis-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

2-Isopropoxy-5-methyl-4-(cis-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)aniline(164 mg, 0.57 mmol),2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (197 mg,0.57 mmol), Xantphos (33 mg, 0.057 mmol), Pd(OAc)₂ (6 mg, 0.029 mmol),and Cs₂CO₃ (555 mg, 1.71 mmol) were dissolved in anhydrous THF (20 mL).N₂ was bubbled through the reaction mixture for 5 min, and then thereaction vessel was sealed and heated under microwave irradiation to150° C. for 30 min. The mixture was filtered and the filtrateconcentrated under reduced pressure. The residue was purified byprep-HPLC (gradient from 10% to 60% acetonitrile in water) to give thetitle compound (50 mg, 15% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.35 (d,J=8.2 Hz, 1H), 8.24 (s, 1H), 7.81-7.89 (m, 1H), 7.76-7.71 (m, 1H), 7.65(s, 1H), 7.51-7.47 (m, 1H), 6.84 (s, 1H), 5.59-5.57 (m, 1H), 4.68-4.64(m, 1H), 4.08-3.95 (m, 2H), 3.42-3.36 (m, 1H), 2.97 (s, 3H), 2.81-2.71(m, 1H), 2.46-2.44 (m, 1H), 2.13 (s, 3H), 1.60 (d, J=6.8 Hz, 3H), 1.50(d, J=5.5 Hz, 3H), 1.33 (d, J=6.0 Hz, 6H), 1.27 (d, J=6.8 Hz, 6H).

Example 7 Synthesis of5-chloro-N²-(4-((cis)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step A: Synthesis ofcis-2,6-dicyclopropyl-1-(4-methoxybenzyl)piperidin-4-one

To a solution of acetone dicarboxylic acid (3.0 g, 20.5 mmol) in water(20 mL) was added cyclopropanecarbaldehyde (2.876 g, 41 mmol). Then4-methoxyphenylmethanamine (2.8 g, 20.5 mmol) was added in smallportions over 10 min. The resulting yellow solution was stirred at roomtemperature for three days. The reaction mixture was extracted withdichloromethane (3×60 mL). Combined extracts were washed with brine anddried with anhydrous Na₂SO₄. The solution was filtered and evaporated togive brown residue. The isomeric piperidones were separated by silicagel chromatography with hexane/ethyl acetate (7/1, v/v). The desiredtitle compound (34.0 g, 54%) was obtained as a pale yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 7.35 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 4.34(d, J=13.9 Hz, 1H), 3.95 (d, J=13.9 Hz, 1H), 3.83 (s, 3H), 2.64-2.38 (m,6H), 0.81-0.77 (m, 2H), 0.71-0.38 (m, 4H), 0.35-0.30 (m, 2H), 0.10-0.03(m, 2H).

Step B: Synthesis of cis-2,6-dicyclopropylpiperidin-4-one

Cis-2,6-dicyclopropyl-1-(4-methoxybenzyl)piperidin-4-one (3.0 g, 11mmol) was dissolved in ethanol (20 mL) and catalyst (0.3 g, 10% Pd—C)was added. The mixture was stirred under hydrogen atmosphere for 12 hr.The catalyst was removed by filtration and the filtrate was evaporatedunder reduced pressure to give the title compound (1.52 g, 91% yield).This product was used directly in the next step without furtherpurification.

Step C: Synthesis oftert-butyl-cis-2,6-dicyclopropyl-4-oxopiperidine-1-carboxylate

Di-tert-butyl dicarbonate (1.73 g, 7.95 mmol) andN,N-diisopropylethylamine (1.71 g, 13.24 mmol) were added to a solutionof cis-2,6-dicyclopropylpiperidin-4-one (1.0 g, 6.62 mmol) indichloromethane (20 mL) and the mixture was stirred at room temperaturefor 12 hr. Solvent was removed under reduced pressure and the residuewas purified by silica gel chromatography with hexane/ethyl acetate(9/1, v/v) to afford the title compound (0.85 g, 51% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.83-3.81 (m, 2H), 2.90 (dd,J=17.4, 6.0 Hz, 2H), 2.54 (dd, J=17.4, 2.7 Hz, 2H), 1.52 (s, 9H),0.91-0.88 (m, 2H), 0.75-0.72 (m, 2H), 0.62-0.43 (m, 4H), 0.18-0.15 (m,2H).

Step D: Synthesis oftert-butyl-cis-2,6-dicyclopropyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution oftert-butyl-cis-2,6-dicyclopropyl-4-oxopiperidine-1-carboxylate (1.7 g,6.77 mmol) in THF (20 mL) was slowly added 2.0 M LDA (3.39 mL, 6.78mmol) in THF at −78° C. After 20 min, a solution of1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(2.417 g, 6.77 mmol) was slowly added to the mixture. The reactionmixture was stirred at 0° C. for 3 hr. The solvent was evaporated underreduced pressure, and the residue was purified by column chromatographywith hexane/ethyl acetate (20/1, v/v) to obtain the title compound (1.6g, 58% yield). ¹H NMR (400 MHz, CDCl₃) δ 5.77 (d, J=4.7 Hz, 1H),4.20-4.18 (m, 1H), 2.82-2.84 (m, 1H), 2.73-2.61 (m, 1H), 2.57-2.49 (m,1H), 1.55-1.53 (m, 1H), 1.49 (s, 9H), 1.09-1.06 (m, 1H), 0.62-0.42 (m,6H), 0.35-0.25 (m, 1H), 0.22-0.11 (m, 1H).

Step E: Synthesis of tert-butylcis-2,6-dicyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

The suspension of tert-butyl-cis-2,6-dicyclopropyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (1.6 g, 4.13 mmol),bis(pinacolato) diboron (1.255 mg, 4.96 mmol), potassium acetate (1.214mg, 12.39 mmol), 1,10-bis(diphenylphosphino) ferrocene (114 mg, 0.21mmol), and [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex in dichloromethane (154 mg, 0.21 mmol) were stirred in1,4-dioxane (20 mL) at 80° C. for 12 hr. The reaction mixture wasextracted with ethyl acetate, and the organic layer was washed withbrine, dried over anhydrous Na₂SO₄, and filtered. The solvent wasevaporated under reduced pressure, and the residue was purified bycolumn chromatography with hexane/ethyl acetate (9/1, v/v) to obtain thetitle compound (1.6 g, 99% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.49 (d,J=4.7 Hz, 1H), 4.07-4.05 (m, 1H), 2.80-2.78 (m, 1H), 2.50-2.38 (m, 1H),2.30-2.28 (m, 1H), 1.48 (s, 9H), 1.39-1.25 (m, 1H), 1.28 (s, 12H),1.08-1.00 (m, 1H), 0.55-0.37 (m, 6H), 0.30-0.20 (m, 1H), 0.14-0.05 (m,1H).

Step F: Synthesis oftert-butyl-cis-2,6-dicyclopropyl-4-(5-fluoro-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

Tert-butyl-cis-2,6-dicyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.35 g, 3.74 mmol), Pd(dppf)Cl₂ (109 mg, 0.15 mmol), and K₂CO₃ (1.55 g,11.22 mmol) were added to a solution of1-bromo-5-fluoro-2-methyl-4-nitrobenzene (1.05 g, 4.49 mmol) in DME-H₂O(22 mL, 10:1 mixture). The mixture was stirred at 80° C. for 12 hr undernitrogen. The reaction was cooled to room temperature and the productwas extracted with ethyl acetate. Solvent was removed under reducedpressure and the residue was purified by silica gel chromatography withhexane/ethyl acetate (9/1, v/v) to afford the title compound (1.20 g,77% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, J=7.5 Hz, 1H), 7.04 (d,J=11.5 Hz, 1H), 5.80-5.65 (m, 1H), 4.30-4.26 (m, 1H), 3.30-3.20 (m, 1H),2.65-2.55 (m, 1H), 2.49 (dd, J=16.2, 5.8 Hz, 1H), 2.37 (s, 3H), 1.53 (s,9H), 1.40-1.30 (m, 1H), 0.95-0.83 (m, 1H), 0.68-0.49 (m, 6H), 0.35-0.14(m, 2H).

Step G: Synthesis oftert-butyl-cis-2,6-dicyclopropyl-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution oftert-butyl-cis-2,6-dicyclopropyl-4-(5-fluoro-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate(670 mg, 1.61 mmol) in 20 mL of 2-propanol was added Cs₂CO₃ (1.574 g,4.83 mmol). The mixture was stirred at 60° C. overnight, and aftercooling to room temperature, most of the 2-propanol was evaporated underreduced pressure. Water was added, and the solution was extracted withethyl acetate. The organic layers were combined, dried over Na₂SO₄,concentrated, and the crude product was purified by silica gelchromatography with hexane/ethyl acetate (9/1, v/v) to afford the titlecompound (700 mg, 95%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.65(s, 1H), 6.82 (s, 1H), 5.70-5.66 (m, 1H), 4.66-4.56 (m, 1H), 4.33-4.30(m, 1H), 3.28-3.20 (m, 1H), 2.67-2.56 (m, 1H), 2.47 (dd, J=16.0, 5.1 Hz,1H), 2.28 (s, 3H), 1.53 (s, 9H), 1.42-1.24 (m, 2H), 1.40 (d, J=6.0 Hz,6H), 0.70-0.44 (m, 6H), 0.34-0.25 (m, 1H), 0.20-0.10 (m, 1H).

Step H: Synthesis oftert-butyl-cis-4-(4-amino-5-isopropoxy-2-methylphenyl)-2,6-dicyclopropyl-3,6-dihydropyridine-1(2H)-carboxylate

To a solution oftert-butyl-cis-2,6-dicyclopropyl-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate(380 mg, 0.833 mmol) in 20 mL of ethanol was added several drops of 10%HCl, followed by iron powder (280 mg, 5.0 mmol). The mixture was stirredat 60° C. for 3 hr. The reaction was cooled to room temperature and theiron powder was filtered off. Ethanol was removed under reduced pressureand the title compound was obtained as a pale yellow oil. This productwas used directly without further purification.

Step I: Synthesis of5-chloro-N²-(4-((cis)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Tert-butyl-cis-4-(4-amino-5-isopropoxy-2-methylphenyl)-2,6-dicyclopropyl-3,6-dihydropyridine-1(2H)-carboxylate(350 mg, 0.822 mmol),2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (283 mg,0.822 mmol), Xantphos (48 mg, 0.0822 mmol), Pd(OAc)₂ (9 mg, 0.0411mmol), and Cs₂CO₃ (801 mg, 2.466 mmol) were dissolved in anhydrous THF(20 mL). N₂ was bubbled through the reaction mixture for 5 min, and thenthe reaction vessel was sealed and heated under microwave irradiation to150° C. for 30 min. The mixture was filtered and the filtrateconcentrated under reduced pressure. The residue was dissolved indichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added and thereaction was stirred at room temperature for 6 hr. The dichloromethaneand trifluoroacetic acid were removed under vacuum. The residue waspurified by prep-HPLC (gradient from 10% to 60% acetonitrile in water)to give the title compound (150 mg, 29% yield). ¹H NMR (400 MHz, CD₃OD)δ 8.36 (d, J=8.3 Hz, 1H), 8.24 (s, 1H), 7.99 (d, J=8.0, 1H), 7.79-7.68(m, 1H), 7.67 (s, 1H), 7.48 (t, J=7.7 Hz, 1H), 6.83 (s, 1H), 5.62 (s,1H), 4.70-4.58 (m, 1H), 3.44-3.35 (m, 2H), 2.90-2.79 (m, 1H), 2.72-2.52(m, 2H), 2.14 (s, 3H), 1.33 (d, J=6.1 Hz, 6H), 1.27 (d, J=6.9, 6H),1.20-1.03 (m, 2H), 0.84-0.71 (m, 6H), 0.54-0.44 (m, 2H).

Example 8 Synthesis of5-chloro-N²-(4-((cis)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step A: Synthesis ofcis-2,6-dicyclopropyl-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine

To a solution oftert-butyl-cis-2,6-dicyclopropyl-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate(390 mg, 0.855 mmol) in dichloromethane (5 mL) was added trifluoroaceticacid (1 mL) and the reaction mixture was stirred at room temperature for6 hr. The dichloromethane and trifluoroacetic acid were removed undervacuum and 100 mL of dichloromethane was added, washed with saturatedNaHCO₃ solution. The water layer was extracted with dichloromethane foradditional two times (100 mL each). The organic layers were combined,washed with brine, dried over Na₂SO₄ and evaporated. The residue wasdissolved in dichloromethane (10 mL) and 37% formaldehyde (208 mg, 2.56mmol), sodium triacetoxyborohydride (290 mg, 1.368 mmol) and acetic acid(82 mg, 1.368 mmol) were then added. The reaction was stirred at roomtemperature overnight. The reaction was quenched by adding water (80mL), and extracted with dichloromethane (3×100 mL). The organic layerswere combined, washed with brine, dried over Na₂SO₄, concentrated andpurified by silica gel column chromatography with ethyl acetate/methanol(9/1, v/v) to afford the title compound (275 mg, 87% for two steps) as ayellow oil. MS m/z=371 (M+H).

Step B: Synthesis of4-(cis-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylaniline

To a solution ofcis-2,6-dicyclopropyl-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine(370 mg, 1.0 mmol) in 20 mL of ethanol was added several drops of 10%HCl, followed by iron powder (336 mg, 6.0 mmol). The mixture was stirredat 60° C. for 3 hr. The reaction was cooled to room temperature and theiron powder was filtered off. Ethanol was removed under reduced pressureand the title compound was obtained as pale yellow oil. This product wasused directly without further purification.

Step C: Synthesis of5-chloro-N²-(4-(cis-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

4-(Cis-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylaniline(270 mg, 0.794 mmol),2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (274 mg,0.794 mmol), Xantphos (46 mg, 0.0794 mmol), Pd(OAc)₂ (9 mg, 0.040 mmol),and Cs₂CO₃ (801 mg, 2.465 mmol) were dissolved in anhydrous THF (20 mL).N₂ was bubbled through the reaction mixture for 5 min, and then thereaction vessel was sealed and heated under microwave irradiation to150° C. for 30 min. The mixture was filtered and the filtrateconcentrated under reduced pressure. The residue was purified byprep-HPLC (gradient from 10% to 60% acetonitrile in water) to give thetitle compound (110 mg, 21% yield). MS m/z=650 (M+H).

Example 9 In Vitro Activity

H3122 and Kappas-299 cells were purchased from American Type CultureCollection (Manassas, Va., USA) and were used within 2 months afterinitiating from original stocks. All cell lines were cultured asrecommended. For cell growth inhibition assay, cells were treated withdifferent concentrations of the tested compounds, diluted from stock toculture media containing a 0.2% DMSO as the final concentration. Cellviability was determined using the WST-8 cell proliferation assay kit(Dojindo Molecular Technologies) according to manufacturer'sinstructions. Three independent experiments in triplicates wereperformed. Data were analyzed using Prism software to determine 50% ofcell growth inhibition (IC₅₀) values versus DMSO control.

TABLE 4 Cpd. Inhibitory activity H3122 (nM) Kappas-299 (nM) No. (nM)(EML4-ALK) (NPM-ALK) 1 1.8 92 30 2 4.4 132 39 5 0.85 27 13 9 1.1 54.935.9 10 0.98 54.9 37.5 15 6.6 196 121 16 6.3 160 97.7

Example 10 Inhibition of Wild-Type and Mutant ALK

The cytoplasmic domain (amino acid 1058-1620) of wild-type human ALKprotein expressed as N-terminal GST-fusion protein was purchased fromCarna Biosciences, Inc (Japan). Mutated ALK proteins were expressed inSF9 insect cells with N-terminal tags cleaved after purification. Kinaseactivities of all enzymes were assessed using a Lance® TR-FRET assay kitfrom Perkin Elmer Life Sciences (Waltham, Mass.). 2.5 μL of compoundsolution and 5 μL of protein solution were added into a black low volume384 well microtiter plate which was incubated for 30 minutes with gentleshaking at room temperature, followed by adding 2.5 μL of fluorescentlylabeled peptide substrate (ULight™-IRS-1 (Tyr983) Peptide) and ATPmixture solution. The kinase reaction was performed in 50 mM HEPES (pH7.5) with 1 mM EGTA, 1 mM MgCl₂, and 2 mM DTT, 0.01% Tween-20 addedright before the assay. Final concentrations of ATP, substrates, andDMSO were 100 μM, 20 nM, and 0.5%, respectively. Concentrations ofdifferent ALK proteins were adjusted accordingly to achieve comparableenzymatic activities for both wild-type and all mutated ALK proteins.Final ALK concentrations were 1 nM, 1 nM, 1 nM, 128 nM, 2 nM, and 4 nMfor wild-type, F1174L, L1196M, 51206Y, G1269A, and G1202R, respectively.The reaction was allowed to perform for 90 minutes in dark with gentleshaking at room temperature after which 10 μL of 20 mM EDTA and 2 nMEu-W1024 anti-phosphotyrosine antibody (PT66) mixture solution in thedetection buffer from the manufacturer was added to terminate thereaction and detect the phosphorylation of the peptide substrate. Thefinal mixture was incubated in the dark for 1 hour before the plate wasread on a Tecan Infinite M-1000 multi-mode plate reader (Tecan, DurhamN.C.) with an excitation wavelength of 320 nm. Emission intensities weremeasured at both 620 and 665 nm with the intensity ratio between 665 and620 nm corresponding to the peptide substrate phosphorylation. IC₅₀values of inhibitors were obtained by fitting the ratio of 665/620 nm vsinhibitor concentrations in a sigmoidal dose-response curve (variableslope) with a non-linear regression. See Tables 5 and 6.

TABLE 5 Enzyme Cpd. No. 5 IC₅₀ (nM) WT  0.85 F1197M 3.3 G1269A 4.3L1196M  0.73 S1206Y 1.3 C1156Y   0.82 (k) V1180L  + (c) F1174L −− (c)G1202R 9.2 + = active; −− = inactive; (c) = cell based assay; (k) =KINOME scan

TABLE 6 Cpd. G1202R No. 5 Crizotinib Alectinib Ceritinib LorlatinibCJ-2360 IC₅₀ 9.2 46.2 34.7 11.5 ± 5.0 2.1 ± 0.4 119 (nM)

Example 11 Kinase Activity

Cpd. No. 5 was screened for its activity against a panel of humankinases using the KINOMEscan™ screening platform from LeadHunterDiscovery Services (currently DiscoverX Corporation (Fremont, Calif.94538, United States). See Table 7.

TABLE 7 Enzyme Cpd. No. 5 K_(d) (nM) ROS1 0.73 FAK 5.4 LTK 0.62 LRRK26.5 LRRK2(G2019S) 6.6 FER 11 FES 12 IGF1R 9 INSR 54 INSRR 32

Example 12 Pharmacokinetics

Routine pharmacokinetics studies were performed for Cpd. No. 5 in SDrats and beagle dogs. See Tables 8 and 9.

Example 13 In Vivo Efficacy

Drug Preparation

Cpd. Nos. 5 and 6 were dissolved in a solution of 98% PEG200: 2% TPGS(Sigma). LDK378 (ceritinib) is a known ALK inhibitor.

Cell Culture

Human lymphoma cells, KARPAS 299 were maintained at 37° C., 95% air, 5%carbon dioxide in RPMI 1640 medium supplemented with 10% Fetal BovineSerum, 100 units/ml of penicillin and 100 units/ml of streptomycin(GIBCO™, Invitrogen Corp.) and passaged twice weekly.

Xenograft Tumor Cell Injection

Tumor cells for xenografts were washed twice in PBS, and re-suspended inan ice cold mixture of 1:1 PBS and Matrigel (BD Biosciences, InvitrogenCorp.) for a final Matrigel protein concentration of 5 mg/ml. Cells at5×10⁶ cells in 0.1 ml were injected subcutaneously (s.c.) into the flankregion of each mouse. All tumors were inoculated into SCID mice(strain:236 C.B-17 SCID, Charles River).

Xenograft Tumor Growth and Weight Monitoring

The size of tumors growing in the mice was measured in two dimensionsusing calipers. Tumor volume (mm³)=(A×B²)/2 where A and B are the tumorlength and width (in mm), respectively. During treatment, tumor volumeand body weight were measured three times a week. After the treatmentwas stopped, tumor volume and body weight was measured at least once aweek.

Assessment of Toxicity and End Point

Tumors were not allowed to exceed 10% of the animal's total body weight.If an animal had two or more tumors the total weight of all tumors werenot allowed to exceed 10% of the animal's total body weight. At the endof the experimental period or when tumor size approached 10% of thetotal body weight, the animal was euthanized. Animals that showedprofound morbidity or a weight loss of over 20% of body weight wereeuthanized.

Determination of In Vivo Antitumor Efficacy

Before treatment began, tumors were allowed to grow to an average of 150mm³ (70-270 mm³) in volume, at which point the blood vessel supplies tothe tumor should have been well established. Mice with tumors withinacceptable size range were randomized into treatment groups of 7 mice.Drug was given orally, once daily for 3 weeks. The Control groupreceived vehicle alone. See FIG. 1.

TABLE 8 Dose Tmax Cmax AUC0-t AUC0-∞ t_(1/2) CL V_(ss) MRT_(INF) (mg/kg)(h) (ng/mL) (ng · h/mL) (ng · h/mL) (h) (iv) (iv) (iv) F Compound IV POIV PO IV PO IV PO IV PO IV PO (L/h/kg) (L/kg) (h) (AUC0-t) Cpd. No. 5 110 0.083 2.67 234 153 506 1759 576 1788 3.94 3.93 1.75 7.97 4.54 31.1%(solution) Cpd. No. 5 10 3.67 75.9 719 733 4.05 12.7 (suspension) Cpd.No. 5 10 1.0 127 958 971 3.84 16.9 (mesylate)

TABLE 9 Dose Tmax Cmax AUC0-t AUC0-∞ t_(1/2) CL V_(ss) MRT_(INF) (mg/kg)(h) (ng/mL) (ng · h/mL) (ng · h/mL) (h) (iv) (iv) (iv) F Compound IV POIV PO IV PO IV PO IV PO IV PO (L/h/kg) (L/kg) (h) (AUC0-t) Cpd. No. 5 15 0.083 1.67 314 239 1821 2929 2137 3711 19.7 20.0 0.486 10.8 22.1 33.3%

It is to be understood that the foregoing embodiments andexemplifications are not intended to be limiting in any respect to thescope of the disclosure, and that the claims presented herein areintended to encompass all embodiments and exemplifications whether ornot explicitly presented herein

All patents and publications cited herein are fully incorporated byreference in their entirety.

What is claimed is:
 1. A method of treating a patient comprisingadministering to the patient a therapeutically effective amount of acompound having Formula I, or a pharmaceutically acceptable salt,hydrate, or solvate thereof, wherein the patient has a cancer in whichanaplastic lymphoma kinase (ALK) has a role and the compound of FormulaI has a structure:

or a pharmaceutically acceptable salt or solvate thereof, wherein:R^(la) and R^(1b) are independently selected from the group consistingof hydrogen, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl; R^(2a) and R^(2b) areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, and C₃₋₈ cycloalkyl; R³ is selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₄₋₈ heterocyclo, R⁴ isselected from the group consisting of C₁₋₄ alkyl, and C₃₋₆ cycloalkyl;R⁵ is halo; R⁶ is selected from the group consisting of C₁₋₄ alkyl, andC₃₋₆ cycloalkyl; and R⁷ is selected from the group consisting ofhydrogen, C₁₋₄ alkyl, and C₃₋₆ cycloalkyl, with proviso that whenR^(1a), R^(1b), R^(2a), and R^(2b) are each hydrogen, then R³ isselected from the group consisting of C₃₋₆ cycloalkyl and C₄₋₈heterocyclo.
 2. The method of claim 1, wherein the cancer is selectedfrom the group consisting of anaplastic large-cell lymphoma, non-smallcell lung cancer, diffuse large B-cell lymphoma, inflammatorymyofibroblastic tumors, neuroblastoma, anaplastic thyroid cancer,rhabdomyosarcoma, breast cancer, colorectal cancer, esophageal squamouscell cancer, and renal cell carcinoma.
 3. The method of claim 1comprising administering a compound having Formula II:

or a pharmaceutically acceptable salt thereof, wherein: R^(1a) andR^(1b) are independently selected from the group consisting of hydrogen,C₁₋₄ alkyl, and C₃₋₆ cycloalkyl; R^(2a) and R^(2b) are independentlyselected from the group consisting of hydrogen, C₁₋₄ alkyl, and C₃₋₆cycloalkyl; and R³ is selected from the group consisting of hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₄₋₈ heterocyclo.
 4. The method ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R^(1b)and R^(2b) are each hydrogen.
 5. The method of claim 4, or apharmaceutically acceptable salt thereof, wherein Ria and R^(1a) andR^(2a) are each hydrogen.
 6. The method of claim 4, or apharmaceutically acceptable salt thereof, wherein R^(1a) and R^(2a) areeach C₁₋₄ alkyl or C₃₋₆ cycloalkyl.
 7. The method of claim 6, or apharmaceutically acceptable salt thereof, wherein R^(1a) and R^(2a) areeach methyl or are each cyclopropyl.
 8. The method of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(la), R^(1b),R^(2a), and R^(2b) are each C₁₋₃ alkyl.
 9. The method of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(la), R^(1b),R^(2a), and R^(2b) are each methyl.
 10. The method of claim 1, or apharmaceutically acceptable salt thereof, comprising administering acompound having Formula III:

wherein: R^(1a) and R^(2a) are each independently selected from thegroup consisting of C₁₋₄ alkyl, and C₃₋₆ cycloalkyl; and the compoundhas an enantiomeric excess of 90% or more.
 11. The method of claim 2, ora pharmaceutically acceptable salt thereof comprising administering acompound, having Formula IV:

wherein: R^(la) and R^(2a) are each independently selected from thegroup consisting of C₁₋₄ alkyl, and C₃₋₆ cycloalkyl; and the compoundhas an enantiomeric excess of 90% or more.
 12. The method of claim 1, ora pharmaceutically acceptable salt thereof comprising administering acompound, having Formula V:

wherein: R^(1a) and R^(2a) are each independently selected from thegroup consisting of C₁₋₄ alkyl, and C₃₋₆ cycloalkyl; and the compoundhas an enantiomeric excess of 90% or more.
 13. The method of claim 1, ora pharmaceutically acceptable salt thereof comprising administering acompound, having Formula VI:

wherein: R^(la) and R^(2a) are each independently selected from thegroup consisting of C₁₋₄ alkyl, and C₃₋₆ cycloalkyl; and the compoundhas an enantiomeric excess of 90% or more.
 14. The method of claim 1, ora pharmaceutically acceptable salt thereof, wherein R³ is hydrogen, C₁₋₃alkyl, or C₃₋₆ heterocyclo.
 15. The method of claim 14, or apharmaceutically acceptable salt thereof, wherein R³ is selected fromthe group consisting of:


16. The method of claim 1, or a pharmaceutically acceptable saltthereof, selected from the group consisting of:5-chloro-N²-(2-isopropoxy-5-methyl-4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-isopropoxy-5-methyl-4-(2,2,6,6-tetramethyl-1,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine:5-chloro-N²-(4-((cis)-2,6-diethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-diethyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-isopropoxy-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-isopropoxy-5-methyl-4-(1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-dicyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-dicyclobutyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-isopropoxy-5-methyl-4-((cis)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-diethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-diethyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-isopropoxy-5-methyl-4-((trans)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dicyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dicyclobutyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-diethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S6S)-2,6-diethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((cis)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dicyclobutyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dicyclobutyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-((trans)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-isopropoxy-5-methyl-4-(2S,6R)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6R)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6R)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6S)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-isopropoxy-5-methyl-4-(2R,6S)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6S)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-isopropoxy-5-methyl-4-(2S,6S)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(2-isopropoxy-5-methyl-4-(2R,6R)-1,2,6-trimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6S)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6S)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6S)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6S)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine5-chloro-N²-(4-(2S,6R)-2,6-dicyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6R)-2,6-dicyclopropyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6S)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4(2R,6S)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6S)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6S)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6R)-2,6-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6R)-2,6-dimethyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6S)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6S)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6S)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2R,6S)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenvl)pyrimidine-2,4-diamine;5-chloro-N²-(4-(2S,6R)-2,6-dicyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine; and5-chloro-N²-(4-(2S,6R)-2,6-dicyclopropyl-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine.17. The method of claim 16, or a pharmaceutically acceptable saltthereof, which is5-chloro-N²-(2-isopropoxy-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine.
 18. A kit comprising the compound having FormulaI or a pharmaceutically acceptable salt thereof, and instructions foradministering the compound, or a pharmaceutically acceptable salt,hydrate, or solvate thereof, to a patient having cancer in whichanaplastic lymphoma kinase (ALK) has a role, wherein the compound ofFormula I has a structure:

or a pharmaceutically acceptable salt or solvate thereof, wherein:R^(1a) and R^(1b) are independently selected from the group consistingof hydrogen, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl; R^(2a) and R^(2b) areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, and C₃₋₈ cycloalkyl; R³ is selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₄₋₈ heterocyclo, R⁴ isselected from the group consisting of C₁₋₄ alkyl, and C₃₋₆ cycloalkyl;R⁵ is halo; R⁶ is selected from the group consisting of C₁₋₄ alkyl, andC₃₋₆ cycloalkyl; and R⁷ is selected from the group consisting ofhydrogen, C₁₋₄ alkyl, and C₃₋₆ cycloalkyl, with proviso that whenR^(la), R^(1b), R^(2a), and R^(2b) are each hydrogen, then R³ isselected from the group consisting of C₃₋₆ cycloalkyl and C₄₋₈heterocyclo.